214

THE DIFFERENTIAL DIAGNOSIS OF JAUNDICE By E. IDRIS JONES, M.D., M.R.C.P.

A knowledge of the ' natural history' of bili- occurs, it is readily excreted by the kidneys when rubin is essential for the clear differentiation of the present in the blood stream, and it gives a direct different types of jaundice. Bilirubin is a break- van den Bergh reaction. down product of haemoglobin, manufactured by 4. Urobilinogen is found in normal urine (in the reticulo-endothelial system mainly in the traces) and is increased in the urine when there is spleen and bone-marrow but also in any other an excess of it in the bowel. organs or tissues of the body where reticulo- endothelial tissue occurs. The haemoglobin 5. Bile salts are found in the urine when post- molecule consists of a porphyrin fraction linked to hepatic bilirubin is also present and at no other globin and iron and it is the porphyrin which is time. converted into bilirubin via heme (haematin). The bilirubin passes from the spleen, bone- Applied Physiology of Bilirubin marrow, etc., in the blood stream, to the liver (a) In haemolytic states. If excessive haemo- where it is passed through the parenchymatous globin destruction occurs in the body an excess of cells of the liver and into the bile capillaries. pre-hepatic bilirubin is formed. The liver ex- (During its passage through the liver cells it is cretes a larger amount of post-hepatic bilirubin altered in a way to be referred to later.) The than normally, more urobilinogen is therefore bilirubin now passes out of the liver in the bile, present in the gut and the faeces are thus darker and in the gut is reduced to urobilinogen (also than normally. Owing to the large amount of called stercobilinogen). Further oxidation con- urobilinogen in the faeces more is absorbed into verts the urobilinogen (stercobilinogen) into uro- the portal vein and more escapes being re- libin (stercobilin) which gives the characteristic excreted by the liver and passes into the general brown colouration to the faeces. Oxidation of blood stream to be excreted eventually by the bilirubin to biliverdin may occur and in certain kidneys. An excess of urobilinogen therefore conditions the faeces may be green for this reason. occurs in the urine. Some of the pre-hepatic Part of the urobilinogen is re-absorbed from the bilirubin reaching the liver fails to pass through gut and is carried back in the portal vein to the the liver cells and becomes converted into post- liver where most of it is re-excreted in the bile hepatic bilirubin, passing instead into the general but some passes through the liver eventually blood stream and causing a rise in the amount reaching the kidneys and is excreted in the urine. present with subsequent development of icterus. The following points need special emphasis: (b) In obstructive conditions. When obstruc- tion to the outflow of bile occurs, post-hepatic bili- i. The bilirubin found in the reticulo-endo- rubin and bile salts are absorbed from the bile thelial tissues is different from the bilirubin which into the general blood stream. Icterus of the skin passes into the bile capillaries and hence into the appears and bilirubin and. bile salts appear in the gut. These two bilirubins are sometimes called urine. The amount of pre-hepatic bilirubin pre-hepatic (or haemobilirubin) and post-hepatic formed of course remains the same. As no bile is (or cholebilirubin). The chemical difference be- reaching the gut, no urobilinogen and urobilin is tween the two is not known but the conversion of found in the gut, so the faeces are pale and devoid the former into the latter occurs during passage of pigment. through the parenchymatous cells of the liver. (c) In toxic conditions affecting the liver. 2. Pre-hepatic bilirubin is normally present in Under these conditions the liver cells undergo the blood (0.2-0.4 mgm.), is not excreted by the cloudy skwelling and the endothelium of the bile and therefore never in the capillaries also swells. The swelling of the liver kidneys, appears urine, cells the and it gives an indirect van den Bergh reaction. compresses bile canaliculi and the bile capillaries so that obstruction to the free outflow 3. Post-hepatic bilirubin is found in the blood of bile occurs and the post-hepatic bilirubin con- only when obstruction of the biliary passages tained therein is absorbed into the blood stream. April 1 948 IDRIS JONES: The Differential Diagnosis ofJaundice 2I5 At the same time, because of the toxic condition (b) Serum jaundice has acquired considerable of the liver cells, some of the pre-hepatic bilirubin importance recently and every jaundiced patient is not absorbed and passed into the biliary system should be carefully questioned as to the ad- so that this bilirubin also appears in the blood ministration of blood, serum, or other intravenous stream in excessive amounts. injections during the previous three months. Again a virus is the responsible agent and its identity Causes of Icterus with the virus of infective hepatitis is probable though not proved. I. False icterus. (a) Icterus or jaundice is often diagnosed when it is not present. Perhaps the (c) Many poisons may affect the liver, leading commonest error is to mistake the yellowish pallor to jaundice. Chief among these are chloroform, present in severe anaemia for jaundice. Examina- phosphorus, trinitrotoluene, arsenic, etc. It must tion of the conjunctivae or, in doubtful cases, an not be forgotten that sulphonamides can act as icteric index estimation, will soon resolve the liver poisons, but probably only in susceptible in- difficulty. dividuals or in patients with previously abnormal livers. Acute yellow atrophy has been observed (b) Staining of the skin may be present and even and reported several times after sulphanilamide. of the conjunctivae in various conditions when the level of bilirubin in the blood is normal. Caro- (d) Jaundice may occur during the course of tinaemia due to excessive ingestion of carotin, and many acute infective processes. To mention a mepacrine administration are two common causes few, Weil's disease, yellow fever, glandular fever, of apparent jaundice which should always be pneumonia, etc. considered. 5. Haemolytic icterus. This arises whenever excessive destruction occurs. 2. icterus. This occurs haemoglobin Physiological normally (a) Physiological jaundice of the new born has after birth but disappears in a few days. It is due been mentioned above. to the destruction of a proportion of the infant's red blood cells consequent upon the cessation of (b) Icterus gravis neonatorum. This is a severe placental respiration. A mild degree of jaundice type of haemolytic anaemia caused by hae- may also occur following infarction of the lungs, maglutinins arising in a Rhesus negative mother severe bruising of the tissues, etc., where extra- in response to antigens from a Rhesus positive vasated blood is converted into bilirubin. foetus. 3. Obstructive jaundice. Any cause of obstruc- (c) Congenital haemolytic icterus (acholuric tion to the outflow of bile from the liver or bile jaundice). The familial incidence and increased ducts will lead to jaundice. A stone or worm in fragility of the red cells, together with spleno- the common bile duct, extrinsic or intrinsic car- megaly and jaundice make this one of the easier cinoma blocking the bile duct, or fibrous tissue conditions to recognize. compressing or strangling the main bile duct or (d) Acquired haemolytic icterus. There are some of its tributaries will all lead to jaundice of many varieties of this condition. In some cases a the obstructive type. Congenital obliteration of definite chemical compound can be incriminated, the bile ducts is a rare type. such as lead, phenylhydrazine, potassium chlorate, 4. Toxic or infective jaundice. (a) In recent sulphonamides, arsenicals and benzene derivatives. years infective hepatitis has been the com- In other cases micro-organisms such as the malarial monest cause of this type of jaundice. In this parasite, Clostridium welchii, etc., may be causa- condition, the parenchymatous cells of the liver tive, and in others no cause can be found and are attacked by a virus leading to swelling and these are usually referred to as ' Lederer's acute poor functioning of the cells. The bile capillaries haemolytic anaemia.' The jaundice of pernicious are compressed by the swelling, and the endo- anaemia is also haemolytic in origin. thelium of the bile capillaries also swells leading (e) Incompatible blood transfusion is usually to further obstruction of the lumen of these obvious with other associated symptoms. vessels. A small amount of bile, however, does reach the common duct in most cases and this bile The Clinical Features of Jaundice may become very thick and inspissated and lead to In all cases of course the history is important. further obstruction of the passages, and a per- The mode of onset, associated with gastro- sistence therefore of jaundice when the liver intestinal or other symptoms, the occupation of the condition itself is returning to normal. Steps patient, any loss of weight, the administration of should therefore be taken in this disease to keep drugs or injections, the family history, etc., should the biliary passages drained, e.g., mag. sulph. all be elicited. On physical examination, the each morning. presence or absence of pyrexia should be noted, 2I6 POST GRADUATE MEDICAL JOURNAL April 1948 also the depth of the jaundice; in particular a in it, the spleen is not palpable and the faeces are careful examination of the abdomen is essential. pale, with the urine very dark and loaded with bile The right hypochondrium must be carefully pal- salts and bilirubin. Itching of the skin is common. pated and the size of the liver noted, together with In haemolytic jaundice there may be a family any evidence of tenderness or irregularity of the history or a history of malaria, drug or chemical organ. The epigastrium must be palpated for a ingestion, the temperature is usually raised while possible neoplasm of the stomach and the left haemolysis is occurring, the jaundice is mild and hypochondrium examined for splenic enlargement. the trunk appears to be more jaundiced than the Glandular enlargement should be looked for and legs, nausea is absent, anaemia is marked, the liver also the presence or absence of anaemia with any is usually only slightly enlarged, if at all, the associated neurological signs or tongue changes. spleen is enlarged, sometimes markedly so, the In all cases the urine and faeces must be examined. faeces are dark and the urine is dark, containing The colour of the faeces-whether pale and putty- an excess of urobilinogen but no bilirubin or bile like, or normal, or darker than normal-and the salts. In acholuric jaundice, ulcers are common presence or absence of bilirubin, bile salts or on the legs, and in pernicious anaemia there is urobilinogen in the urine are the main points to glossitis and signs of subacute combined degenera- be looked for. Having elicited the history and tion of the cord. completed a physical examination, we can in the Laboratory aids in differential diagnosis. If majority of cases decide if the jaundice is toxic, the points mentioned above are clearly noted, a haemolytic or obstructive in origin. Clinically, case of jaundice can usually be ascribed to one of therefore, in toxic jaundice there may be a history the three main classes without any laboratory aid. of drug or chemical poisoning, the temperature is Difficult cases do occur, however, particularly in commonly raised, 'the jaundice is moderately differentiating between toxic and obstructive deep, nausea is present, anaemia is slight or absent, jaundice. Indeed, obstruction is a feature of most the liver is enlarged and tender, the spleen is not cases of toxic jaundice and sometimes even palpable, the faeces are pale and the urine is dark laboratory aids do not help in distinguishing the and contains bilirubin and, maybe, bile salts. In two types and the subsequent history of the case certain diseases there may be associated signs such has to be relied on in deciding the final diagnosis. as skin haemorrhages or herpes-as in Weil's If the jaundice gradually lessens it was toxic in disease. In obstructive jaundice there may be a origin, but if it remains deep after a month then history of biliary colic, or loss of weight, or loss of obstruction is almost certainly present and appetite, suggesting either impaction of a calculus, laparatomy is advisable to determine the cause. or a neoplasm of the pancreas or stomach. The Urine and faeces examination has been dealt with temperature is normal or subnormal, the jaundice in the clinical section. A complete blood count is is marked and deepens rapidly, nausea may be always advisable and may give valuable aid. A absent, anaemia may or may not be present, the marked anaemia with increased fragility of the liver is usually a little enlarged and may have red cells and a reticulocytosis would indicate palpable metastatic carcinomatous masses present haemolytic icterus. A leucocytosis also occurs in

SUMMARY OF MAIN DIAGNOSTIC FEATURES IN JAUNDICE Obstructive. Toxic or Infective. Haemolytic. I.Mode of onset. Rapid with or without pain. Gradual, jaundice deepening Gradual. fairly rapidly. 2. Nausea. Slight or moderate. Marked. Absent. 3. Temperature. Normal. Commonly raised. Raised only in acute hae- molytic states. 4. Degree of icterus. Great. Slight or great. Moderate. 5. State of liver. Little enlarged, may have Enlarged and tender. Normal. metastatic nodules. 6. Spleen. Not palpable. Rarely palpable. Palpable, often grossly en- larged. 7.- Faeces. Pale. Pale. Dark. 8. Urine. Dark, contains bile pigment Dark, contains bile pigment Dark, but contains no and bile salts. No uro- and bile salts. May be bile pigment or salts. bilinogen present. trace of urobilinogen Urobilinogen present in present. excess. 9. Blood count. Normal or slight anaemia. Normal but maybe leucocy- Anaemia with reticulocy- tosis. tosis. Io. Duration of icterus. Persists until obstruction is Clears usually in less than a May persist for years. relieved. month. April 1948 Book Reviews 217 haemolytic icterus during the acute stage but in preted in conjunction with the history and physical the absence of anaemia a leucocytosis of i5,ooo or examination. In toxic jaundice a prompt direct over would indicate malaria, Weil's disease or reaction is often obtained and in obstructive suppurative pylephlebitis. The van den Bergh jaundice a biphasic reaction may occur. reaction on the serum has rightly gained the most Of the other aids to diagnosis little need be said. important place in the laboratory diagnosis of A cholecystogram may reveal a calculus; blood jaundice. A prompt direct reaction indicates or urine culture will show leptospira in Weil's obstructive jaundice, a biphasic reaction probably disease; blood films will be positive in malaria, toxic jaundice and an indirect reaction, haemo- etc. Ivtic jaundice. But too much reliance must not be The main diagnostic features in jaundice may placed on the test and it must always be inter- be summarized in the foregoing table.

BOOK REVIEWS

DIAGNOSIS IN STERILITY English language. For this book of 440 small pages, approximately 150,000 words, attempts to Edited by EARLE T. ENGLE. Blackwell Scientific cover the whole subject including anatomy and Publications. I947. Pp. 236. Price 25s. treatment and in doing so sacrifices clarity and This book chronicles the proceedings of a con- accuracy. Many examples of this can be given. On ference sponsored by the National Committee on page 43 ' In other instances a virus infection Maternal Health, and is concerned with diagnosis appears to be the cause ' is read in the paragraph on only. The conference was attended by every well- the causation of the common cold. Surely this is known worker in the field of sterility in the U.S.A. an inadequate comment on the part played by the The proceedings are presented verbatim and are virus. On page 44 in the paragraph on Treatment all the more interesting on this account, and there of Acute Rhinitis this sentence appears, ' If possible is a most useful summary of the conference. the patient is put to bed with a hot drink and a Chapters on laboratory examination of semen and mild laxative, and is nursed in an even tempera- the clinical interpretation of such analyses are ture (Prescription-Camphor j per cent., Menthol sound and rational. There are excellent chapters on i per cent., paraff. lig. i ounce).' The context in the value of testicular and endometrial biopsies and no way clarifies this sentence and the reviewer the discussion on the interpretation of basal body would not know whether to prescribe this as the temperature curves is excellent in every respect. hot drink, the laxative or as nasal drops which are Most English readers will appreciate the attitude not mentioned. On page 114 this sentence ap- of' debunking 'which has pervaded the conference, pears in reference to frontal sinus operations, ' One and has consequently resulted in a high standard of of the most convenient places to start the opening scientific attainment. is just on the outer edge of the orbital roof, almost Most British readers will also take heart when above the inner canthus.' This is a strange juxta- they find that during the war years there was no position of inner and outer where they do not have advance in the U.S.A. over the progress maintained opposite meanings as outer in reference to orbital in this country in the subject of infertility. edge is opposed to deep (not inner as there is no This is a most readable publication with ex- inner edge to the orbit) and inner in reference to is illustrated canthus is opposed to lateral (or outer). cellent references, and throughout it On the whole the illustrations are good and most beautifully by first class photomicrographs. helpful. A notable exception is Fig. 49 (i) on page C.D.R. 239, which fails to show the falling forwards of the cartilage of Wrisberg and apparent shortening of the DISEASES OF THE NOSE, THROAT AND EAR paralysed cord in the resting larynx. It is always easy to criticize adversely a textbook By I. SIMSON HALL, M.B., CH.B., F.R.C.P.E., and the preceding examples of defects could be F.R.C.S.E. 4th Edition. E. & S. Livingstone multiplied but there are also many good features in Ltd. Edinburgh. 1948. Price I5s. the book and pages 372 and 373 on the local signs This book was first published in I937 and the of acute mastoiditis should be particularly com- fourth edition is now published. This is a measure mended for emphasizing the important points of its popularity and a comment on the lack of an clearly and concisely and omitting nothing adequate student's textbook on this subject in the important.