Postgrad. med. J. (May 1968) 44, 347-362. Postgrad Med J: first published as 10.1136/pgmj.44.511.347 on 1 May 1968. Downloaded from

Biochemistry of hyperthyroidism and hypothyroidism* FREDERIC L. HOCH B.S., M.S., M.D. Biophysics Research Division, Institute ofScience and Technology, The University of Michigan, Ann Arbor, Michigan 48104 Summary effect. The preponderance of evidence at present The thyroid hormones act directly on mito- supports the first hypothesis. It seems feasible chondria, and thereby control the transformation therefore to attempt to reduce the complex of the energy derived from oxidations into a form pathologic pictures to subcellular phenomena utilizable by the cell. Through their direct actions and their consequences. on mitochondria, the hormones also control in- Recent advances in the understanding of where directly the rate of protein synthesis and thereby and how the thyroid hormones act in the cell the amount of oxidative apparatus in the cell. A support a simplification of thyrotoxicosis and rationale for the effects of thyroid hormone excess hypothyroidism, although our understanding is or deficiency is based upon studies of the not as yet so far advanced as to permit a final mechanism of thyroid hormone action. In hypo- 'explanation' of the diseases in molecular terms. thyroidism, slow fuel consumption leads to a low A brief history of the evolution of studies on Protected by copyright. output of utilizable energy. In hyperthyroidism, the mechanism of thyroid hormone action serves rapid fuel consumption leads to a high energy to outline the present state of knowledge, the output, but as efficiency decreases, the utilizable areas in which future advances may be made, energy produced decreases. Many of the chemical and a basis for a rationale of hyperthyroidism and physical features of these diseases can be and hypothyroidism. reduced to changes in available energy. Actions and effects of thyroid hormones Introduction Ever since Magnus-Levy (1895) showed that Excess or deficiency in the amount of thyroid the thyroid gland controlled the rate of oxygen hormones in humans produces clinical and consumption in mammals, attention has been chemical manifestations that involve a number fixed on oxidative processes as a target of the of organ and metabolic systems. Variations of hormone. Kendall (1929) showed the structure of thyroid hormone concentrations in vivo change thyroxine and suggested the hormone might be http://pmj.bmj.com/ oxygen consumption, temperature regulation, a component or coenzyme of an oxidative growth and development, the response to other enzyme, undergoing a redox cycle between the hormones, nerve function, and the metabolism of phenol and semiquinone forms. No evidence proteins, fats, carbohydrates, nucleic acids, vita- has as yet been found to support Kendall's hypo- mins, and inorganic anions and cations. On the thesis conclusively. In the years 1940-50 it be- other hand, thyroxine and triiodothyronine are came clear that 90% or more of the cell's relatively simple molecules, and their small size oxygen was consumed via processes occurring on September 30, 2021 by guest. and limited number of reactive groups suggest in mitochondria, and experiments were done either that the variety of the effects they pro- with thyroid hormones in vivo and in vitro to duce are due to a few types of primary inter- determine their effects on mitochondria. actions at the molecular level, or that the hor- One should differentiate, in considering these mones are changed in the body to analogues studies, between actions of the hormones and each having a different and specific physiologic effects of the hormones. Actions may be defined as those functional or structural changes that *Abbreviations: L-T,, L-thyroxine; L-T,, L-triiodo- are primary and depend upon the presence of thyronine; Triac, triiodothyroacetic acid; ATP, ADP and the hormone at a site where it interacts with a AMP, adenosine tri-, di- and mono-phosphate; P1, inorganic molecule in the cellular apparatus. Because hor- phosphate; NADH and NADPH, reduced nicotinamide- mones are effective in small amounts we adenine dinucleotide and dinucleotide phosphate; DNP, may 2,4-dinitrophenol; BMR, basal metabolic rate (0O con- assume that their primary molecular interactions sumption). are reversible, so that the hormones are not 348 Frederic L. Hoch Postgrad Med J: first published as 10.1136/pgmj.44.511.347 on 1 May 1968. Downloaded from used up. Effects may be defined as those func- 1966), then increases in ribosomal RNA-content tional, structural, or compositional changes that and aggregation (about 40 hr) (Tata, 1967). How- are secondary and do not depend upon the pres- ever, although all these phenomena showed an ence of the hormone; they should not be important relationship between the thyroid hor- reversed if the hormone is removed after acting. mones and the processes supplying information The differentiation between actions and effects to and controlling the rate of protein synthesis, makes no judgement on their relative importance they did not show the primary locus of hormone in the cell. The thyroid hormones are peculiarly action. When L-T3 was added to isolated nuclei, suitable for the resolution of primary actions RNA-metabolism was not stimulated (Widnell & from secondary effects, because their iodine Tata, 1963; Tata & Widnell, 1966; Sokoloff, moieties can be used experimentally as a tracer Francis & Campbell, 1964). Tata's conclusions for quantitative analysis. Methods for detecting are diagrammed in Fig. 1. other hormones not possessing this useful pro- perty are less specific or more tedious. As will be detailed below, the thyroid hor- T- -/- Nucleus -:> Ribosome = Protein > Mitochondrion mones were shown to affect mitochondria as synthesis 2,4-dinitrophenol did: both agents increased mitochondrial respiration, and the energy lib- 3-16 40 48 70-90 erated was transformed into heat rather than Time(hr) /i vivo into the normal utilizable form, the high-energy phosphate bond. This toxic, catabolic, energy- FIG. 1. Sequence of events after injecting hypothyroid wasting effect served as a rationale for thyro- rats with thyroid hormone (T = L-T,), according to toxicosis (Hoch, 1962a), but not for the anabolic Tata and co-workers. energy-conserving effects that the smaller doses Protected by copyright. of thyroid hormones exerted in euthyroid or The studies of Sokoloff (Sokoloff & Kaufman, hypothyroid subjects (Hoch, 1962b). Nor was 1959, 1961; Sokoloff et al., 1963, 1964) have hypothyroidism made more understandable by recently drawn attention back to the mitochon- the 'uncoupling' hypothesis. Accordingly, atten- drion as a site of action of the hormone (Fig. 2). tion was directed away from the mitochrondrion in the search for the mechanism. o2 In the early 1960s the groups of Tata and of ASH.2 t-RNA-AA showed that hormones affected T Mitochondrion =>xn > Sokoloff thyroid ATP Ribosomez= Protein synthesis protein synthesis. It had been demonstrated GTP earlier by Dutoit (1952) that protein was syn- 5min Time 2hr: thesized abnormally slowly in the livers of hypo- in vitro in vivo thyroid rats. L-T3 given in vivo accelerated FIG. 2. Sequence of events after injecting hypothyroid http://pmj.bmj.com/ the synthesis of proteins by ribosomes after rats with thyroid hormone, or after addition of thyroid about 48 hr after injection; the doses necessary hormone to mitochondria (T - L-T,), according to were small and physiologic, smaller than those Sokoloff and co-workers. producing uncoupling in mitochondria, and the effect of the hormone was obviously anabolic Adding L-T3 to a homogenate in vitro stimu- (see Tata, 1967). Puromycin and actinomycin D, lated ribosomal synthesis of proteins. The pro- agents that block protein synthesis by acting on cesses whereby t-RNA-amino-acyl complexes

nucleic acids, blocked the calorigenic action of interacted with the ribosomes were the locus of on September 30, 2021 by guest. thyroid hormones (Tata, 1963; Weiss & Sokoloff, the stimulation. Mitochondria oxidizing a sub- 1963). No changes were observed in mitochon- strate were necessary, and they apparently pro- drial respiratory control after hormone injec- duced a substance that accelerated the ribosomal tion (Tata et al., 1963). Respiratory acceleration translation; adding ATP, GTP or glutathione did could be demonstrated in mitochondria 70-90 not replace the effect of hormone-treated mito- hr after hormone injections, but it was due to chondria. What it is that mitochondria produce increases in the number of depleted respira- to control ribosomal protein synthesis is not yet tory assemblies in the mitochondria of hypo- clear; studies by Bronk (1963) have suggested thyroid rats (Tata et al., 1963; Roodyn, Freeman that mitochondrial non-phosphorylated, high- & Tata, 1965), and so represented the specific energy intermediates may support protein syn- results of earlier protein synthesis. Increases in thesis. nuclear RNA-metabolism were shown early (3- Our recent studies have shown that L-T4 in- 16 hr) after hormone injection (Tata & Widnell, jected in vivo can act rapidly and directly on Biochemistry of hyperthyroidism and hypothyroidism 349 Postgrad Med J: first published as 10.1136/pgmj.44.511.347 on 1 May 1968. Downloaded from mitochondria (Hoch, 1968a). Bronk (1966) has not yet clear, the rate of translation of t-RNA- also shown a very short latent period for L-T8. amino-acyl complexes by ribosomes to synthesize In hypothyroid rats, a subcalorigenic dose of proteins. Among the proteins synthesized are L-T4 (at least fifty times less than those used the enzymatic components of the mitochondrial to stimulate protein synthesis) partly corrected respiratory chain. The nucleus is also involved the excessive respiratory control in liver mito- early, but the relation between the rises in nuclear chondria 3 hr after injection (Hoch, 1966). A RNA-metabolism and the earlier changes in larger dose did the same when the rats were mitochondrial function, as well as the later killed 2 min after injection (Hoch, 1967, 1968b). changes in ribosomal metabolism and mitochon- The hormone content of mitochondria, as mea- drial composition, are also not yet finally de- sured by the total iodine or the butanol- fined. Thus, mitochondria show changes in func- extractable iodine, was 20% of normal in un- tion dependent upon the hormone's presence or treated hypothyroid rats, and rose progressively absence, and changes in enzyme content secon- with the functional changes up to 3 hr after dary to the alterations in protein synthesis that injection (Hoch, 1967; Dillon & Hoch, 1968); the depend ultimately upon the functional changes. amount of hormone was one to five molecules It now appears profitable to consider mito- per respiratory assembly in the treated rats, and chondrial respiration and energy-transformation about 50 /uM in the mitochondrion (a concen- as the loci at which the thyroid hormone nor- tration effective in vitro in Sokoloff's experi- mally acts, and at which excess or deficiency in ments). This early or instantaneous action of the hormone content exerts its primary action. hormone was completely reversed when bovine serum albumin was added to the mitochondria, Early functional changes and the of the hormone was Mitochondria be as greater part thereby may regarded energy Protected by copyright. removed (Hoch & Motta, 1968). The features transforming or transducing machines perform- of the reversibility of the functional changes ing oxidative phosphorylation: liberating energy demonstrated the following: (a) that the hor- by oxidizing a substrate, and transforming this mone acted directly on mitochondria, but per- energy into a chemically utilizable form for haps through an intermediate or synergistically endergonic reactions, the high-energy phosphate with endogenous mitochondrial components; (b) bonds of adenosine-triphosphate (ATP). The that synthesis of a mitochondrial protein was molecular events of this process are the subject not involved; and (c) that observations (Tata et of intensive investigation (see Lehninger, 1964; al., 1963) that the hormone produced new mito- Racker, 1965) but are as yet incompletely under- chondrial enzymes demonstrated an effect and stood. Oxidative phosphorylation is measured by not an action of the hormone, because those the rate of oxygen consumption (energy input workers had routinely added bovine serum al- per unit of time) and the efficiency of energy bumin to their assay mixtures and so had ob- transfer, the P:O ratio (utilizable energy output http://pmj.bmj.com/ served only the late irreversible effects of L-T3. per energy input). The amount of work the At the present time, the actions and the effects machine can do per unit of time (the utilizable of the thyroid hormones appear to be related energy output per unit of time) is in physical as in Fig. 3. Low doses of the hormone act units, power. The useful output of the mito- chondrion, its oxidative power, consists of high- energy phosphate bonds. t-RNA-AA Physiologically, the most important feature of T Mitochondrion Ex=> = oxidative is that it is on September 30, 2021 by guest. -. phosphorylation ? - self-regulat- ? ? _ Ribosome => Protein synthesis Nucleus- - ing. The rate of output of high-energy phos- phate bonds controls the rate of input, i.e. the 2 min Time /n v/vo consumption of oxygen and the oxidation of substrates. ADP controls the rate of oxidation; FIG. 3. Sequence of events after injecting hypothyroid ADP accepts the high-energy phosphate groups rats with thyroid hormone (T = L-T4), according to from a hypothetical mitochondrial intermediate Hoch and co-workers. to form ATP. In the absence of added ADP, or in the absence of any agency removing the rapidly or instantaneously, and reversibly, on terminal phosphate groups of ATP to form ADP, mitochondria (only liver mitochondria have so mitochondria oxidize substrates very slowly far shown unmistakable results of treating hypo- (State 4) as in Fig. 4. Addition of ADP, or the thyroid rats with the hormone). The functional presence of an enzyme system hydrolysing ATP changes in mitochondria accelerate, by a process to ADP, increases the rate of oxidation markedly 350 Frederic L. Hoch Postgrad Med J: first published as 10.1136/pgmj.44.511.347 on 1 May 1968. Downloaded from

(State 3) as in Fig. 5. The respiratory control mitochondria subsequently isolated from the ratio is the ratio of the rates of respiration in treated animal phosphorylate with decreased effi- State 3: State 4. The mitochondria in resting ciency. living cells function as if little ADP were avail- The efficiency of oxidative phosphorylation able; that is, cells respire in State 4, in a con- also controls the oxidative rate. Uncoupling trolled condition in which large demands for raises the respiratory rate markedly (State 3u), utilizable energy (production of ADP) can be and depresses the respiratory control ratio (Fig. met with bursts of high oxidative activity (see 6); addition of ADP does not then accelerate Hoch, 1968b). the already rapid respiration. Low concentrations of uncoupling agents, insufficient to decrease the efficiency of phosphorylation measurably, also increase oxygen consumption and lower respira- H2 X P tory control; this is termed 'loose coupling' (Fig. 7). The mechanism that ordinarily limits the rate tsA ) of respiration when ADP is absent (i.e. when -X,-.P remains undischarged) now permits both rapid respiration and transfer of energy. SH2 Oxidation Phosphorylation H 0 ; FIG. 4. Normal mitochondrial oxidative phosphorylation in State 4, with no P-acceptor. The - X P group exerts a on braking effect the oxidation cycle. °2 / j Protected by copyright.

ADP 02 H2O° ( SH2

FIG. 6. Uncoupled oxidative phosphorylation in the ')ATP absence of ADP (State 3u). The -X group exerts no braking effect on the oxidation cycle. Adding ADP will not accelerate oxidation. Phosphorylation is abolished (efficiency = 0). Pi SH2

FIG. 5. Normal oxidative phosphorylation in State 3, in the presence of ADP. The free - X group exerts no braking effect on the oxidation cycle, and oxidation is http://pmj.bmj.com/ accelerated. H20° Pf The efficiency of phosphorylation, the P:O ratio, is the number of moles of high-energy 02p phosphate produced per gram atom of oxygen SH2 consumed. This ratio is 3 for most compounds FIG. 7. Loose-coupled oxidative phosphorylation in the oxidized via diphosphopyridine-nucleotide-depen- on September 30, 2021 by guest. absence of ADP (State 4). The - X P group now dent dehydrogenases. The translation of the exerts no braking effect on the oxidation cycle. Adding energy liberated by oxidation into phosphoryl- ADP will not accelerate oxidation. Phosphorylation is bond energy has been termed 'coupling' by at almost normal efficiency. mechanical analogy (Loomis & Lipmann, 1948). Phosphorylation can be decreased or abolished L-T4 and L-T3 can act like uncoupling agents selectively without diminishing mitochondrial oxi- in many respects. Large doses in vivo and high dations. Physical agencies (e.g. heat or hypotoni- concentrations in vitro uncouple oxidative phos- city) or a variety of chemical agents (the classical phorylation (see Hoch, 1962b; Hoch & Lipmann, one is 2,4-dinitrophenol) 'uncouple' oxidative 1954; Maley & Lardy, 1953; Martius & Hess, phosphorylation, and decrease the phosphoryla- 1952). By either route, the hormone accelerates tion quotient by decreasing its numerator. Many the State 4 oxidation of most substrates and de- of the chemical agents also uncouple in vivo presses the respiratory control. Much smaller when administered to normal animals, i.e. the doses or concentrations also lower respiratory Biochemistry of hyperthyroidism and hypothyroidism 351 Postgrad Med J: first published as 10.1136/pgmj.44.511.347 on 1 May 1968. Downloaded from control by raising State 4 oxidation, but they Qo2) and the efficiency of the machine (the do not depress the P: ratio (see Fig. 7), nor ,PP:O ratio) are plotted as a function of the interfere with the inhibitory action of oligomycin concentration of an agent that can uncouple, (Hoch, 1968b), an agent specific for phosphory- e.g. DNP or thyroid hormone. It will be seen lating respiration. that low concentrations of DNP or thyroid hor- Mitochondria from hypothyroid animals, that mone stimulate energy consumption before effi- contain only 20% of the normal amount of ciency is depressed; the result is increased power. thyroid hormone, are 'over-coupled', respiring Higher concentrations uncouple and depress too slowly in State 4 with excessive respiratory efficiency. Power therefore is decreased, and it control (Maley & Lardy, 1955), as in Fig. 8. It is this catabolic effect that is seen in thyrotoxi- cosis. In hypothyroid subjects, mitochondrial energy consumption is depressed below normal, H2 0 = but efficiency is normal. Power is therefore de- creased. Treatment with L-T4 raises energy con- sumption, but does not affect efficiency: power is restored to normal, an anabolic action. DNP has - been shown to possess such an anabolic 02 %Pp action as well, in accelerating protein synthesis SH2 in vitro (Sokoloff & Kaufman, 1961). However, the differences between the thyroid FIG. 8. 'Over-coupled' oxidative phosphorylation in hormones and the uncoupling agents should be State 4. The - X - P group now exerts a greater than stressed at this normal braking effect on the oxidation cycle. Adding point: certain effects of the thy- ADP will accelerate oxidation to (almost) normal roid hormones are biologically specific. Agents levels. Phosphorylation is normal. like DNP do not relieve all the defects seen in Protected by copyright. hypothyroid subjects, nor do they stimulate seems that the optimal amount of L-T4 is neces- growth and development, nor do they induce sary to poise mitochondrial energy-transfer be- metamorphosis in Anura. The specificity must tween inertia and inefficiency. reside in the differences between their actions at Consideration of oxidative power as an index the mitochondrial level. The mechanisms of of the performance of the mitochondrial mech- action of thyroxine and DNP are known to anism offers a basis for rationalizing many of differ: thyroxine makes mitochondria swell and the diverse effects of the thyroid hormones. In DNP does not; and thyroxine and DNP act Fig. 9, oxidative power is viewed as a resultant synergistically on mitochondrial respiration, not of changes in the rate of oxidation and/or the additively. efficiency of energy transfer (Hoch, 1962a, At least two factors may govern the effect 1968a). The rate of energy consumption (the of thyroid hormones: the thyroid state of the organism (presumably a function of the concen- http://pmj.bmj.com/ % of tration of thyroid hormone in contact with the normal Energy target sites) and the additional amount of the / consumed administered hormone reaching the target. Thus, / (Q02) thyroid hormone given to a hypothyroid subject / raises oxidative metabolic power to normal levels; -P/ 10 Efficiency similar dosage in a euthyroid subject increases / above decreases normal; on September 30, 2021 by guest. 9Q02_o_ / (NP/0) power higher dosage power. Late compositional changes DNP: O ==Cr- The functional changes in mitochondrial res- piration discussed in the previous section involve Thyroid -Hypo -Eu Hyper -- specific respiratory activity, in the sense of the state rate of respiration per amount of respiring mass. Power j-- I- The thyroid hormones also affect the total res- (-P/t) piratory mass in the mitochondrion. They con- trol, the amount of FIG. 9. Fuel consumption (Qo,), efficiency (- P:O), through protein synthesis, and power (- P:t) of the mitochondrion as a function respiratory enzymes per gram of total protein of the concentration of DNP or thyroid hormone (from in the mitochondrion. In hypothyroidism, the Hoch, 1968a). rate of protein synthesis is lower than normal. 352 Frederic L. Hoch Postgrad Med J: first published as 10.1136/pgmj.44.511.347 on 1 May 1968. Downloaded from Mitochondria from hypothyroid rats contain The increased rates of oxidation are accom- half as much cytochrome b, c, and a+a3 as nor- panied by increased production of heat per unit mal mitochondria (Maley, 1957; Kadenbach, of time even when efficiency is normal, and rela- 1966) and perhaps less flavoprotein catalysts (Riv- tively more heat than utilizable energy will be lin & Langdon, 1966). But, paradoxically, there evolved as the efficiency of energy transfer de- is twice the normal amount of pyridine nucleo- creases. In the most extreme forms of thyro- tide coenzymes. Conversely, in mild hyperthyroid- toxicosis, where more complete uncoupling might ism, with its raised rate of protein synthesis, occur, heat production leads to hyperpyrexia (as the content of cytochromes and flavoproteins is in thyroid crisis; see below). Lesser degrees of high, and of pyridine nucleotides, low (Kaden- heat production are compensated by sweating, bach, 1966; Maley & Lardy, 1955). vascular changes, dilation, flushing, and resultant At first glance, these compositional differences tachycardia, increased cardiac stroke volume and seem to reflect or account for the abnormal pulse pressure. Such changes may in part be BMRs in thyroid disease. However, the situation mediated through the action of the hormones is not so clear. The flavoproteins and cyto- of the adrenal medulla (see pp. 357-8). Compen- chromes have turnover numbers, and are pre- sation may be precarious, and the excessive de- sent in such amounts in mitochondria, that they mands imposed by relatively slight increases of do not control or limit oxidation in the respira- external temperature, the rise of heat produc- tory chain. The 'bottle-neck' in respiration (actu- tion during muscular exercise, or administration ally in electron-transport) appears to be at or of agents with uncoupling properties may have near the pyridine nucleotide end of the chain drastic consequences. Increased tissue heat em- (Chance, 1965), and there is evidence that the phasizes the increased metabolic demands and substrate-dehydrogenase interactions are involved further accelerates oxidative rate. Weight loss (Klingenberg, 1963). The pyridine nucleotides, and wasting of both fat and lean body massProtected by copyright. however, change in amount in a direction oppo- (Wayne, 1960) occur without any losses in site to the changes in BMR, under thyroid hor- appetite. mone influence. Thus, while the hormone seems Conversely, the hypothyroid subject consumes to control the maximal capacity for oxidation in oxygen more slowly than normally because his mitochondria, it also controls the specific acti- mitochondria respire slowly in State 4. Both be- vity of respiration in the chain, and the latter cause of thyroid hormone deficiency and res- accounts for the rate of oxygen consumption in piratory enzyme depletion, 'hypometabolism' is the resting subject (Ernster & Luft, 1964). The here not a misnomer, phosphorylative metabolism importance of capacity for oxidation in pro- proceeding at a low rate because of the cesses involving large demands for energy, how- diminished liberation of oxidative energy. De- ever, should not be minimized. creased rates of oxidation produce less heat, and The resting hyperthyroid subject thus con- extremes result in hypothermia (see myxoedema sumes oxygen faster because the mitochondria coma, below). Demands for increased heat pro- http://pmj.bmj.com/ in his tissues consume oxygen faster in State 4. duction, as in acclimatization to cold environ- The term 'hypermetabolism' in this connection is ments, are met poorly by hypothyroid subjects. a misnomer, for while oxidation is increased, the Responses to the hormones of the adrenal metabolic processes of phosphorylative energy medulla are subnormal. It is of some interest transfer are normal or decreased. This kind of that clinical investigators (Selenkow & Marcus, hyperoxidation arises from the presence of ex- 1960) have commented upon the 'apathetic' cess amounts of thyroid hormones in the mito- hyperthyroidism seen in older patients. It has on September 30, 2021 by guest. chondria. Not all organs consume more oxygen features similar to those of hypothyroidism; on in thyrotoxic subjects; the brain, spleen and our basis, both are reflections of the decreased testes do not. The mitochondria of brain, spleen capacities for the production of utilizable energy. and testes do not swell in the presence of thyroid hormones, in contrast to those from other tissues Alterations in metabolism (Tapley & Cooper, 1956), but it is not known Certain features of clinical and experimental if their iodine contents are high or normal in hyperthyroidism and hypothyroidism may be thyrotoxic subjects. Another kind of hyperoxi- considered as manifestations of changes in the dation may arise from the late adaptive increases transformation of energy. More information is in mitochondrial enzyme content, but it is pre- available on the correlation of manifestations sumably fully efficient and should persist for and basic changes in hyperthyroidism than in some time even when the amount of thyroid hypothyroidism. The following are those areas hormone in the mitochondria becomes normal. of energy utilization best studied at present. Biochemistry of hyperthyroidism and hypothyroidism 353 Postgrad Med J: first published as 10.1136/pgmj.44.511.347 on 1 May 1968. Downloaded from Protein metabolism contents of the livers of thyroxine-treated rats Thyroid hormones control protein synthesis (Handler, 1948), and the fat content of human and breakdown. The effect of administered thy- bodies (Wayne, 1960) were below normal in roid hormones depends upon the thyroid status hyperthyroidism. Thyroidectomy also decreased of the subject. Low doses of thyroxine stimulate the rate of cholesterol synthesis (Boyd, 1959); protein synthesis, high doses depress it. L-Ts the low rate of synthesis of cholesterol and fatty decreased protein synthesis in euthyroid humans, acids in myxoedematous subjects was raised to but the same dose raised the low rate of protein normal by thyroid hormones (Lipsky et al., 1955) synthesis to normal levels in myxoedematous However, the control of lipid synthesis by thy- patients (Crispell, Parson & Hollifield, 1956). In roid hormones has also been observed in tissue hypothyroid rats, 5-10 ,ug of T4 daily increased preparations that were supposed to be free of protein synthesis (Karp & Stetten, 1949; Rupp, mitochondria (Fletcher & Myant, 1960). Paschkis & Cantarow, 1949), but in either hypo- The defects and increases in lipid synthesis thyroid or normal animals, 50-100 j/g decreased might be ascribed to changes in the availability or abolished synthesis (Rupp et al., 1949; Soko- of ATP at various steps in the process, even if loff & Kaufman, 1959). Hyperthyroid humans mitochondria were not present in the lipid- have subnormal amounts of parenchymal pro- synthesizing preparations. Thus, the effects of tein in liver biopsies (Nikkila & Pitkanen, 1959). thyroid hormones have been laid to alterations Consistent with the decreased synthesis of pep- in the supply of acetyl-coenzyme A, or further tide linkages, the concentrations of free amino along the synthetic path, in the conversion of acids in blood, liver and muscle are elevated in acetate to cholesterol, fatty acids and CO2 (Day- thyrotoxic rats (Crispell et al., 1956; Friedberg ton et al., 1960); both require ATP. Coenzyme A & Greenberg, 1947). Rat muscle (Ferrini, Per- concentrations do vary in the tissues of thyro- roni & Bestagno, 1959) and human cells growing toxic animals, being low in hyperthyroid rat Protected by copyright. in culture (Leslie & Sinclair, 1959) incorporate livers (Fraenkel-Conrat & Greenberg, 1946) and amino acids into proteins more slowly in the in hyperthyroid humans (Gershberg & Kuhl, presence of added thyroxine. Sokoloff & Kauf- 1950), and rising above normal when thyroidec- man's (1961) studies have demonstrated in vitro tomized rats are treated with thyroxine, appar- that the apparently conflicting effects of T4 upon ently via increased availability of ATP (Tabach- protein synthesis are in reality biphasic hor- nick & Bonnycastle, 1954). monal effects. The fatty acid oxidases are in mitochondria. Thyroid hormones can act directly on lipid oxid- Lipid metabolism ations by controlling ATP production, since fatty Thyroid hormones control the rates of lipid acid activation requires ATP prior to oxidation. synthesis, oxidation and mobilization. Biphasic Thyroxine treatment accelerated fatty acid oxid- effects of thyroid hormone have been shown on ation in rat heart homogenates (Deitrich & Smith, lipid synthesis (Fletcher & Myant, 1960); 20 /ug 1960), earlier than it raised the basal metabolic http://pmj.bmj.com/ of thyroxine increased the synthesis of choles- rate (Abelin & Kiirsteiner, 1928). Bacterial oxid- terol from acetate by the cell-free fractions of ation of cholesterol was increased by added rat livers, while 30-50 /,g decreased the syn- thyroid hormones (Wainfan & Marx, 1955). thesis. Fatty acid synthesis was decreased at all Hypothyroidism decreased fatty acid oxidation these levels of dosage. and ATP production from fatty acids in the Thyroid-treated rats and humans synthesized hearts of dogs. cholesterol more than normal hormones also control acid con-

rapidly (Kritch- Thyroid fatty on September 30, 2021 by guest. evsky, 1960), and the hypocholesterolaemia of centrations in tissues through the rate of the thyrotoxicosis, anomalous in the face of increased mobilization of fatty acids from adipose tissue, synthesis, was ascribed to the hormonal stimu- in conjunction with the action of other hor- lation of cholesterol excretion (Rosenman, Byers mones. T3 and Triac raised serum concentra- & Friedman, 1952). Increased rates of choles- tions of unesterified fatty acids within 6 hr in terol and fatty acid synthesis have been ob- humans (Rich, Bierman & Schwartz, 1959) and served in hormone-treated rats and in their tissue enhanced their release from adipose tissue and slices (Karp & Stetten, 1949; Dayton et al, 1960). their removal from serum in dogs. These On the other hand, decreased rates of choles- thyroid effects are facilitations of other stimuli, terol synthesis were observed in liver homo- particularly epinephrine (Jeanrenaud, 1961), genates (Scaife & Migicovsky, 1957) and cell- which ordinarily liberate fatty acids (Schwartz free preparations (Fletcher & Myant, 1962) from & Debons, 1959). Epinephrine-induced mobili- thyrotoxic rats. The cholesterol and neutral fat zation of fatty acids in vivo requires optimal 354 Frederic L. Hoch Postgrad Med J: first published as 10.1136/pgmj.44.511.347 on 1 May 1968. Downloaded from thyroid function, while thyroid hormone alone contents of liver and muscle were markedly does not release fatty acids from adipose tissue diminished in hyperthyroid subjects, especially in vitro (White & Engel, 1958). Hypothyroidism the metabolically active forms of glycogen (Chil- prevents epinephrine-induced mobilization. In son & Sacks, 1959), but this, of course, may also hypopituitary monkeys epinephrine injection depend on increased breakdown. Consistent with liberated no fatty acids; thyroid-stimulating hor- a decrease in synthesis is the fact that both liver mone partly restored, and small doses of T3 and muscle (where the major portion of gly- fully restored, the normal fat-mobilizing res- cogen synthesis proceeds) showed decreased con- ponse to epinephrine (Goodman & Knobil, tents of ATP after thyroid hormones were ad- 1959). Hyperthyroidism exaggerates the epine- ministered (Chatagner & Gautheron, 1960; Berg, phrine effect on fat pads in vitro (Debons & 1937). Increases in synthetic rates have also been Schwartz, 1961) and hypothyroidism abolishes it. observed, however, after single doses (Stern- The fat-mobilization effects of insulin are simi- heimer, 1939) or more prolonged hormone treat- larly affected by the thyroid state, insulin re- ment followed by liver perfusion with large leasing six times more free fatty acids from the amounts of glucose (Burton, Robbins & Byers, adipose tissue of T4-injected rats than normally 1958). (Hagen, 1960). These interdependences of hor- The hyperglycaemic effect of epinephrine, mone effects may reflect the facts that fat mobi- mediated through the increased formation of lization depends upon the production of cyclic- cyclic-3',5'-AMP and the subsequent activation 3',5'-AMP, and that cyclic-3',5'-AMP is formed of phosphorylase, depends upon the thyroid only from ATP; the thyroid hormones control state, and administered thyroid hormone pro- ATP production, and it may be speculated-in duces biphasic effects. A small dose of T4 raised the absence of definite information to date- the hyperglycaemic effect of injected epinephrine that the ATP supply, as well as the hormone- whereas in rabbits fed 225 g of desiccated thy-Protected by copyright. controlled activity of adenyl cyclase, controls roid, epinephrine caused little or no hypergly- cyclic-3',5'-AMP production. caemia (Burn & Marks, 1925; Abbot & Van Buskirk, 1931). The amount of liver glycogen Carbohydrate metabolism also affects the hyperglycaemic response to epine- Thyroid hormones control the rates of gly- phrine; prolonged thyrotoxicosis depletes rabbit cogen synthesis and breakdown, and of hexose liver glycogen and then no hyperglycaemia fol- oxidation. lows epinephrine administration. In hypothyro- Thyroxine has a biphasic effect on glycogen dism, epinephrine produced a response smaller synthesis. Low doses of thyroxine increased gly- than normal. cogen synthesis in rat diaphragms either in vivo Thyroid hormones affect hexose oxidation and or in vitro, and higher doses reversed this effect hexose phosphorylation, directly and by modifica- (Wertheimer & Bentor, 1953). In vivo injections tions of the actions of other hormones. Oxidation of thyroid-stimulating hormones (in normal but of hexoses was accelerated by administered thyroid http://pmj.bmj.com/ not in thyroidectomized animals), or of 20-30 /ug hormone, either through equal increases in both of L-thyroxine, increased glycogen synthesis, the phosphogluconate and the glycolytic path- whereas 100-200 /ug of L-thyroxine decreased ways, or mainly through increased glycolysis; the synthesis below normal rates. In vitro, incuba- route chosen may depend upon the degree of tion of 2 /ig of L-thyroxine with normal hyperthyroidism, low doses of hormone acceler- rat diaphragms increased glycogen synthesis ating glycolysis mainly (Glock, McLean & White while amounts either did not and higher stimulate, head, 1956) depressing the phosphogluconate on September 30, 2021 by guest. or irregularly depressed, synthesis. Both the in path (Dow & Allen, 1961). Hypothyroidism de- vitro and the in vivo effects depended upon in- pressed glucose exidation via both paths (Dow cubation of the diaphragms in homologous rat & Allen, 1961). The mechanisms of the thyroid serum, which may have involved thyroxine-bind- hormonal effects on glycolysis may be via one ing or lipid-binding. The lack of a measurable or more routes. An effect of thyroxine on the rise in oxygen consumption, however, indicates cytoplasmic acylphosphatase of rat liver and caution in accepting this system as one depend- muscle has been demonstrated: administered ing simply on ATP-supply. hormone increases acylphosphatase activity, thy- Most of the available evidence indicates de- roidectomy decreases it, and then low doses of creased synthesis of glycogen in thyrotoxicosis. T4 restore it (Harary, 1958). This enzyme hydro- Glycogen synthesis was decreased in hyperthy- lyses 1,4-diphosphoglycerate to Pi and 3-phos- roid humans and rabbits (Coggeshall & Greene, phoglycerate; it acts as a rate-limiting ATPase, 1933; Mirsky & Broh-Kahn, 1936). The glycogen uncoupling glycolysis from phosphorylation, and Biochemistry of hyperthyroidism and hypothyroidism 355 Postgrad Med J: first published as 10.1136/pgmj.44.511.347 on 1 May 1968. Downloaded from accelerates both glycolysis (by supplying Pi) and ism, skeletal muscles are larger and firmer than mitochondrial oxidation (by supplying ADP). normal and contract slowly because of an ab- And the activity of two enzymes of the glyco- normality in the contraction mechanism (Milli- lytic pathway, enolase and lactic dehydrogenase, kan & Haines, 1957). The clinical sign of the were increased in the livers of thyrotoxic rats 'hung-up' reflex, with its slow relaxation, reflects (Bargoni et al., 1961), but they are probably not this defect. In hyperthyroidism, muscle contracts rate-controlling steps; the activities of a number at the normal rate, but performs work ineffi- of the glycolytic enzymes were decreased in hypo- ciently (Plummer & Boothby, 1923). Clinically, thyroidism (Bargoni et al., 1964). Lastly, the 'thyrotoxic myopathy' (Thorn & Eder, 1946; Hed, hormonal control of the generation of NADH Kirstein & Lundmark, 1958) reflects this defect. and NADPH by mitochondria might also affect Thyroxine has a biphasic effect on muscular both glycolysis and the phosphogluconate path- work in adrenalectomized rats, a low dose im- way (Dow & Allen, 1961). Increased glucose proving the work done per contraction, and a uptake or oxidation, or both, have been ob- four-times-higher dose decreasing it (Ganju & served in the muscles and in the livers of hyper- Lockett, 1958). thyroid animals, and also in cultures of animal The relation between muscle contraction and cells, sperm, Saccharomyces cerevisiae, or Ace- thyroid state thus seems clearer than in the case tobacter aerogenes treated with thyroid hormones. of some of the synthetic processes, probably be- The rates of glucose utilization may also be cause muscle contraction and relaxation depend affected through a hormonal control of hexose more directly upon ATP supplied by mitochon- phosphorylation. Thyrotoxicosis raised the acti- drial oxidative phosphorylation. The other source vity of intestinal phosphokinases (Nishikawara & of muscle ATP, the r-P of phosphocreatine, can Gabrielson, 1961), and the observed delays in support only a few contractions and must itself the tolerance curves for glucose and galactose be replenished from mitochondrial energy trans- Protected by copyright. in this condition have been ascribed to rapid formations. The skeletal muscles of thyrotoxic phosphorylation and intestinal absorption (Alth- rats showed uncoupling (Johnson et al., 1958), ausen, 1940). However, the importance of the and those of thyrotoxic humans showed loose phosphokinases in absorption has been ques- coupling (Ernster, Ikkos & Luft, 1959). In our tioned (Nishikawara & Gabrielson, 1961). The terms, these mitochondria showed the action of utilization rate of glucose, measured under con- the excessive amounts of thyroid hormones pre- stant intravenous load, is reported to be normal sent. Other studies on apparently similar patients in thyrotoxicosis (Macho, 1958) and normal in have shown normal muscle mitochondrial res- hypothyroidism (Macho, 1961); in hypothyroid- piratory control, and either high controlled (State ism, administration of thyroxine or DNP rapidly 4) and maximal (State 3) respiration (Stocker, (4 hr) accelerated the utilization rate, suggesting Samaha & De Groot, 1966) or normal levels of that these two agents act similarly. respiration (Dow, 1967; Peter & Lee, 1967); be- Intravenous glucose-tolerance tests gave high cause bovine serum albumin was used in the http://pmj.bmj.com/ disappearance rates in hyperthyroid patients and preparation and assay of the mitochondria, these low rates in hypothyroids; tolbutamide decreased results may show only the underlying enzymatic blood glucose faster in hyperthyroids and slower composition of the muscle mitochondria as con- in hypothyroids; and glucagon induced a lower trasted with the action of the excessive amounts glucose response in hyperthyroids (Lamberg, of hormone present in situ. 1965). Orally administered D-xylose was norm- Heart muscle mitochondria are particularly absorbed with or to ally by patients thyrotoxicosis susceptible thyroid hormones (Bing, 1961). on September 30, 2021 by guest. myxoedema, but oral or intravenous D-xylose Clinically, this seems to be reflected in the high was excreted in the urine more rapidly in thyro- incidence of myocardial failure in thyrotoxicosis toxicosis, and less rapidly in myxoedema (Broit- (the increased work load and decreased effi- man et al., 1964). Thyroid hormones potentiate ciency of contraction are an unfortunate com- insulin action; insulin-induced hypoglycaemia was bination), and in the lack of response of this increased in human thyrotoxicosis (Elrick, Hlad form of failure to digitalis (which is more effec- & Arai, 1961), and the uptake of glucose by rat tive against mechanically induced defective con- adipose tissue was more sensitive to insulin after tractile mechanisms). thyroxine was injected (Hagen, 1960). Alterations in creatine metabolism usually in- volve muscle. A rationale for the observations Muscle contraction and creatine metabolism is shown in Fig. 10. Clinically and experimentally, Thyroid hormones control muscle contraction hyperthyroidism is accompanied by increased and creatine metabolism. In human hypothyroid- creatine excretion, and hypothyroidism by de- 356 Frederic L. Hoch Postgrad Med J: first published as 10.1136/pgmj.44.511.347 on 1 May 1968. Downloaded from creased creatine excretion. In hyperthyroidism, al., 1960). Pyridoxal-5-phosphate content was low creatine synthesis was normal (Wilkins & Fleisch- because of defective phosphorylation; conversely, mann, 1946). Injection of thyroxine rapidly de- it was high after thyroidectomy (Labouesse, pleted muscle phosphocreatine content, well be- Chatagner & Jolles-Bergeret, 1960). Vitamin fore creatine excretion rose (Wang, 1946), sug- B12 content was low in the tissues of thyro- gesting a hormonal effect of phosphorylation. toxic rats and hypothyroid female rats (Gershoff Thyrotoxic humans excreted creatine admini- et al., 1958; Kasbekar et al., 1959); hormone stered to them, or endogenously synthesized, in administration raised renal B12 to normal in contrast to normal subjects, because of an in- hypothyroid rats, and above normal in euthy- ability to 'fix' creatine in their muscles, i.e. to roid rats (Okuda & Chow, 1961). Ascorbic acid resynthesize phosphocreatine from creatine and content was low in the blood and tissues of ATP (Shorr, Richardson & Wolff, 1933; Thorn, thyrotoxic subjects. Pantothenic acid and CoA 1936). The defective creatine load-test is so char- metabolism have been discussed under 'Lipid acteristic that it has been used diagnostically. metabolism', and follow the same general pat- tern as the other water-soluble vitamins. The thyroid hormones also control the syn- thesis of a fat-soluble vitamin. Vitamin A syn- ADP thesis requires thyroid hormone. Both hypo- and hyperthyroid patients had poor dark adaptation C-* ATATPP,I Muscle C * contraction (Wohl & Feldman, 1939). In hypothyroidism serum vitamin A was decreased because carotene was not converted to the vitamin; hormone treat- Pi ---Pi +Cr ment restored synthesis (Drill & Truant, 1947; ^ 1[ Johnson & Baumann, 1947). In euthyroid animals, Protected by copyright. E xcretion the hormone increased vitamin A synthesis, but prolonged treatment produced a severe resistant FIG. 10. Creatine and inorganic phosphate ion meta- vitamin A deficiency (Portugal'skaya, 1961), an- bolism in relation to mitochondrial energy transfer. other example of the hormone's biphasic effect. Creating phosphate (Cr - P), usually in equilibrium with the generated ATP, dissociates in hyperthyroidism to maintain the ATP level. The extra free creatine (Cr) Metabolism of inorganic ions and phosphate (Pi) are excreted. The Pi pool is aug- Phosphorus metabolism is strongly influenced mented through inefficiency of oxidative re-esterification. by the thyroid state. Hyperthyroid patients are Similarly, administering extra Cr in a load test augments in negative phosphorus balance (Rawson et al., the Cr-pool and subsequent excretion. 1955). Hypothyroid patients excreted large amounts of phosphate soon after administration Vitamin metabolism of the hormone, probably because of increased The thyroid hormones control the utilization phosphocreatine hydrolysis (Beaumont, Dodds & http://pmj.bmj.com/ of the water-soluble vitamins and their synthesis Robertson, 1940; Flach et al., 1959). Phosphate into coenzymes. The synthetic steps affected are contents were high, and ATP contents were low, usually energy-requiring condensations and phos- in the soft tissues of thyrotoxic animals (Berg, phorylations. Most of the information is avail- 1937; Chatagner & Gautheron, 1960; Maley, able on thyrotoxic subjects, where conditioned 1957). The esterification of phosphate was slow vitamin deficiences exist (Drill, 1943; Rawson, in such tissues (Johnson et al., 1958). In the Rall & Normal intake of vita- Sonenberg, 1955). bones of hyperthyroid patients, phosphate was on September 30, 2021 by guest. mins is accompanied by deficiency symptoms turned over abnormally rapidly (Hernberg, 1960) because of increased demands or defective utili- probably in conjunction with the changes in zation. calcium. Thiamine requirements are increased in hyper- Calcium metabolism also changes in thyroid thyroid patients. The blood and liver vitamin disease. Calcium turnover in bones is accelerated contents were subnormal, and the excretion was in hyperthyroid patients, and becomes normal higher than normal (Williams et al., 1943). Tis- with the thyroid state upon treatment (Krane sue cocarboxylase content was low in hyper- et al., 1956). Calcium accumulation was more thyroid rats; it rose after thiamine was injected, striking in the livers than in the bones of thyro- but then fell more rapidly than in euthyroid xine-treated rats; the capacity of liver mitochon- animals, suggesting rapid destruction (Peters & dria to store Ca++ may be involved. In hypo- Rossiter, 1939). Pyridoxine availability is limited thyroid rats, calcium incorporation into bone in the tissues of hyperthyroid animals (Wohl et was decreased (Lengemann, Wasserman & Biochemistry of hyperthyroidism and hypothyroidism 357 Postgrad Med J: first published as 10.1136/pgmj.44.511.347 on 1 May 1968. Downloaded from Comar, 1960) but in hypothyroid humans, hor- and to antagonize adrenomedullary hormones mone administration did not raise calcium ex- have also been used with success. cretion rapidly, although it raised phosphate ex- The experimental induction of the acute cretion (Beaumont et al., 1940), perhaps because hyperthermia that is seen clinically in thyroid the hormone acts more directly on phosphate crisis provides an insight into how the thyroid metabolism. hormones act physiologically. Administering large Magnesium metabolism depends upon the doses of thyroid hormone to animals usually thyroid state, and vice versa. Mg++ and thyroid produces a loss of weight and an apathetic death, hormones are antagonists in vivo and in vitro not a hyperthermic crisis. Much smaller doses when mitochondrial function is measured (see of hormone, however, can produce fatal hyper- Hoch, 1962b). Myxoedematous patients excreted thermia in conjunction with the administration large amounts of Mg++ in their urine promptly of an agent that acts on mitochondrial oxidative after hormone administration (Tapley, 1955). The metabolism. Among such compounds are the un- plasma magnesium content was low in hyper- coupling agents, like dinitrophenol (Hoch, 1965a) thyroidism and high in hypothyroidism; Mg bal- dinitro-o-cresol (Barker, 1946) and methylene ance was positive in hyper- and negative in blue (Alwall, 1936); phosphate ions given by in- hypothyroidism; total and cellular exchangeable fusion (Roberts et al., 1956); and antipyretic Mg++ was strikingly low in hypothyroidism but agents, like sodium salicylate (Hoch, 1965a). A normal in hyperthyroidism (Jones et al., 1966). dose of salicylate too small to raise the BMR The effect of administering magnesium salts upon in a normal rat raises the BMR sharply in a thyrotoxicosis is controversial, some finding a midly hyperthyroid rat; one-quarter of the nor- decrease in BMR and heart rate (Hueber, 1939), mally lethal dose of salicylate rapidly induces others finding no decrease in BMR nor change a fatal hyperthermia in such hyperthyroid rats. in negative nitrogen and phosphate balances With dinitrophenol, this phenomenon can be Protected by copyright. Wiswell, 1961). shown to arise from an exaggerated sensitivity Decreased exchangeable potassium (Munro, of mitochondria to the uncoupling agent, in- Renschler & Wilson, 1958; Wayne, 1960) and duced by thyroxine treatment (Hoch, 1968c). hyperkalaemia and hyperkaluria (Boekelman, Whether the clinical phenomenon has a similar 1948) have been reported in thyrotoxicosis. Oc- basis remains to be seen. The association of casionally periodic muscular paralysis is asso- thyroid crisis in thyrotoxic patients with infec- ciated with hyperthyroidism. tions that cause fever (Means, De Groot & Stan- bury, 1963) may be another example of an in Temperature regulation vivo synergism. The thyroid hormones are involved in the In hypothyroidism, heat production is control of body temperature. About 60% of the diminished by the depressed rate of mitochon- energy liberated by mitochondrial oxidations is drial oxidations. Again there are physiologic normally converted to a chemically utilizable compensations to preserve body heat, and the http://pmj.bmj.com/ form, the other 40% being liberated as heat and skin is cold, circulation is slow, and cold is thereby maintaining the body temperature of poorly tolerated. Body temperatures may be homeotherms. In hyperthyroidism heat produc- below normal. Infections that normally elicit tion is raised by two factors: the increased rate fever may not raise the hypothyroid patient's of oxidation and the decreased efficiency of temperature at all, or at least not above normal. energy conversion. Usually the excess amounts Occasionally a fatal hypothermia may supervene, of heat can be dispelled by physiologic com- the so-called myxoedema coma, in which

body on September 30, 2021 by guest. pensations such as flushing, sweating and in- temperature can no longer be maintained, and creased circulation; many of the clinical char- has been reported as low as 74°F. Experiment- acteristics of hyperthyroid patients arise from ally the calorigenic response of hypothyroid rats these compensations. to an administered uncoupling agent is sub- Thyrotoxic crisis or storm can be viewed as a normal (Hoch, 1965b), because their mitochon- failure of compensation due to increased heat dria are subnormally sensitive (Hoch, 1967, production through a further loss of mitochon- 1968c). Administered thyroxine rapidly raises drial efficiency. Body temperatures rise sharply mitochondrial responses, and the efficiency of to 107°F or more, muscle tone is lost, liver such treatment clinically may be evidence for a damage (? mitochondrial) is severe and the common basis for the hypothermia. patients may die. Body refrigeration may remove enough heat to save the situation, but therapeutic Effects of hormones and drugs measures to provide adrenocortical hormones The effects of a number of hormones and 358 Frederic L. Hoch Postgrad Med J: first published as 10.1136/pgmj.44.511.347 on 1 May 1968. Downloaded from drugs depend upon the thyroid state of the sub- The adrenal cortical hormones and insulin may ject, as has been mentioned above in connec- have synergistic effects with the thyroid hor- tion with specific systems. In general, hyper- mones on a physiological level, but these effects thyroidism exaggerates and hypothyroidism min- involve different rates of catabolism and produc- mizes the changes seen after administration of tion of all three groups of hormones, as well the agent. Physiologically, the clearest example as interactions in the tissues. is that of the catecholamines. The relationship is so striking that some have concluded that the Other features apparent peripheral effects of thyroxine are There are several clinical features of hyper- actually effects of epinephrine (Brewster et al., thyroidism and hypothyroidism that are not 1956), but there is evidence against so sweeping readily reduced to manifestations of changed cel- a claim (see Hoch, 1962b). The biochemical lular energy transfer. These features fall into basis of the observed interdependences may be two categories. First, there are those that arise the inactivating effects (or actions?) of thyroid from mechanisms not due directly to the hormones upon the enzymes that normally in- changed amounts of thyroid hormones in the activate the catecholamines themselves. The cate- tissues, but to phenomena associated with the chol-o-methyl-transferase (D'Iorio & Leduc, primary defect in thyroid hormone production. 1960), the amine oxidases (Zile & Lardy, 1959), Thus, exophthalmos is one of the classical signs and a peroxidase system (Klebanoff, 1959) have in the Merseburg triad in hyperthyroidism but it been studied, but it is still difficult to assign is not produced by hormone administration physiologic relevance to the mechanisms. (Means et al., 1963). A pituitary factor, possibly Another enzymatic system under scrutiny in this associated with thyrotropin, may be responsible regard involves the formation of cyclic-3',5'- (Loeb & Friedman, 1932). The frequent persist- AMP, the mediator of many of the catechol- ence of exophthalmos after the therapeutic res- Protected by copyright. amine effects. Thyroid hormones have been sug- toration of euthyroidism speaks for such a gested to control the activation of the lipase in secondary relationship. adipose tissue via a mechanism involving cyclic- In the second category are those clinical fea- 3',5'-AMP (Fisher & Ball, 1967). Yet other pos- tures that may (and indeed seem to) arise from sible routes are the control the thyroid hormones changed amounts of tissue thyroid hormone, but exert over ATP availability, since ATP is the that are not reducible to cellular phenomena be- only source of cyclic-3',5'-AMP; and the sen- cause we don't know enough yet. The hyper- sitivity of mitochondria. Adrenochrome and irritability of the nervous system in hyperthyroi- thyroxine act synergistically on mitochondria in dism, and its opposite in hypothyroidism, may vitro (Park, Meriwether & Park, 1956). The be presenting symptoms clinically. The involve- glycogenolytic and hyperglycaemic, the lipolytic, ment of ATP in nerve conduction and in re- the inotropic, and the calorigenic effects of epine- synthesis of acetylcholine at the myoneural junc- phrine all depend upon the thyroid state (see tion, and the involvement of K+, Ca++ and Mg++ http://pmj.bmj.com/ Ellis, 1956; Brodie et al., 1966; Goodman & in neural events make it likely that hormone- Bray, 1966). The abnormally slow pulse rate induced defects in energy transfer and ion ac- after epinephrine administration in hypothyroid cumulation will affect the nervous system, but patients, and the rapid rate in hyperthyroid sub- just how changes in nerve function relate to jects, have been used diagnostically, although 'nervousness' presents complex problems not yet caution is advised in hyperthyroids (Goetsch & conclusively approached. Similarly, the present- Ritzmann, 1934). ing abnormality of seems to be a 'myxoedema' on September 30, 2021 by guest. The dependence of the calorigenic effect of defect in mucopolysaccharide metabolism that epinephrine upon the thyroid state is an example leads to excessive deposition, somehow and pre- of the generality that the thyroid state controls sumably dependent upon insufficient thyroid the response of the body to calorigenic sub- hormone. stances. Excessive rise in BMR is seen in hyper- The thyroid hormones obviously control thyroidism, and little or no rise is seen in hypo- growth, development, and the striking structural thyroidism, after the administration of glucagon and chemical changes in Anuran metamorphosis. (Davidson, Salter & Best, 1960), nitrophenols, In general terms we may say these processes salicylates (Hoch, 1965a, b), chloropromazine must depend upon available 'energy' but our (unpublished data), and 'febrile toxins' (above). lack of knowledge of the details of the energy- The only exception seems to be the enhanced dependent steps precludes a mechanistic inter- sensitivity of hypothyroid subjects to the thyroid pretation at present. In this area, however, the hormone itself. recent evidence that the thyroid hormones con- Biochemistry of hyperthyroidism and hypothyroidism 359 Postgrad Med J: first published as 10.1136/pgmj.44.511.347 on 1 May 1968. Downloaded from trol mitochondrial energy metabolism directly CHANCE, B. (1965) Reaction of oxygen with the respiratory and promptly, and thereby regulate protein syn- chain in cells and tissues. J. gen. Physiol. 49, 163. new in- CHATAGNER, F. & GAUTHERON, D. (1960) Influence des thesis, offers promise of and important hormones thyroidiennes sur la teneur en adenosine tri- formation on biologic and medical problems. phosphate du foi du rat. Biochim. biophys. Acta, 41, 544. CHILSON, O.P. & SACKS, J. (1959) Effect of hyperthyroidism Acknowledgment on distribution of adenosine phosphates and glycogen in This work was supported by research Grant AM-11184 liver. Proc. Soc. exp. Biol. (N. Y.), 101, 331. from the National Institutes of Arthritis and Metabolic COGGESHALL, H.C. & GREENE, J.A. (1933) The influence of Diseases, National Institutes of Health, Bethesda, Maryland, desiccated thyroid gland, thyroxin, and inorganic iodine, U.S.A. upon the storage of glycogen in the liver of the albino rat under controlled conditions. Amer, J. Physiol. 105, 103. CRISPELL, K.R., PARSON, W. & HOLLIFIELD, G. (1956) A References study of the rate of protein synthesis before and during ABBOT, A.J. & VAN BUSKIRK, F.W. (1931) The blood sugar the administration of L-triiodothyronine to patients with response to epinephrin in thyroid-fed animals. Amer. J. myxedema and healthy volunteers using N-15 glycine. med. Sci. 182 610. J. clin. Invest. 35, 164. ABELIN, I. & KURSTEINER, P. (1928) Ober den Einflusz der DAVIDSON, I.W.F., SALTER, J.M. & BEST, C.H. (1960) The Schilddrusensubstanzen auf den Fettstoffwechsel. Biochem. effect of glucagon on the metabolic rate of rats. Amer. J. Z. 198, 19. clin. Nutr. 8, 540. ALTHAUSEN, T.L. (1940) The disturbance of carbohydrate DAYTON, S., DAYTON, J., DRIMMER, F. & KENDALL, F.E. metabolism in thyrotoxicosis. J. Amer. med. Ass. 115, 101. (1960) Rates of acetate turnover and lipid synthesis in ALWALL, N. (1936) Ober die Wirkung der Dinitrophenole normal, hypothyroid and hyperthyroid rats. Amer. J. auf die Tierischen Oxydationsprozesse. Skand. Arch. Physiol. 199, 71. Physiol. Suppl. 72, 1. DEBONS, A.F. & SCHWARTZ, I.L. (1961) Dependence of the BARGONI, N., GRILLO, M.A., RINAUDO, M.T., FOSSA, T., lipoytic action of epinephrine in vitro upon thyroid AYASSOT, M. & Bozzi, M.L. (1964) Glycolysis and hormone. J. Lipid Res. 2, 86. glycogenesis in the liver of hypothyroid rats. Boll. Soc. ital. DEITRICH, R.A. & SMITH, D.L. (1960) Effect of the thyroid Biol. sper. 40, 1888; (Chem. Abstr., 64, 2506e, 1966). on butyrate oxidation in the rat heart. Biochem. Pharmacol. BARGONI, N., LUZZATI, A., RINAUDO, M.T., RossINI, L. & 3, 85. Protected by copyright. STRUMIA, E. (1961) tber die Leberglykolyse von mit DILLON, R.S. & HOCH, F.L. (1968) Iodine in mitochondria Schildruse gefutterten Ratten. Hoppe-Seylers Z. physiol. and nuclei. Biochem. Med. (In press). Chem. 326, 65. D'IORIO, A. & LEDUC, J. (1960) The influence of thyroxine BARKER, S.B. (1946) Effect of thyroid activity upon metabolic on the o-methylation of catechols. Arch. Biochem. Biophys. response to dinitro-ortho-cresol. Endocrinology, 39, 234. 87, 224. 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