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ACCME/Disclosures

ACCME/Disclosures

ACCME/Disclosures The USCAP requires that anyone in a position to influence or control the content of CME disclose any relevant financial relationship WITH COMMERCIAL INTERESTS which they or their spouse/partner have, or have had, within the past 12 months, which relates to the content of this educational activity and creates a conflict of interest. Dr. John A. Hart declares he has no conflict(s) of interest to disclose. Metabolic – microvesicular steatosis considered JOHN HART, M.D. SURGICAL & UNIVERSITY OF CHICAGO MEDICAL CENTER [email protected] 13-15855 Clinical History • 13 y.o. F with elevated LCTs tests noted during a routine check-up • TB = 0.5, AST = 56, ALT = 67 • Abnormal lipid profile: – Cholesterol = 274 – Triglycerides = 169 – LDL = 209 • Normal BMI of 18.6 • PE revealed • U/S showed fatty infiltration of the liver

Cathepsin D LAMP-2 Ceroid in Kupffer cells LIPA mutations • Lysosomal acid lipase deficiency: – Wolman disease – Cholesterol ester storage disease • Autosomal recessive inheritance: – chromosome 10q23.2-q23.3 – Mutation prevalence in U.S of up to 1 in 200 – 25 cases per 1 million live births N Engl J Med 373;11 nejm.org September 10, 2015 Cholesterol Ester Storage Disease

• Diagnosis: – High serum cholesterol (300 mg/dL) – High serum LDL (225 mg/dL) – Low serum HDL (30 mg/dL) – High serum triglycerides (200 mg/dL) – Hepatomegaly, splenomegaly, adenopathy – Elevated liver chemistry tests – Early onset liver and cardiac disease • Natural history: – Accelerated atherosclerosis and – Statin drugs ineffective – Enzyme replacement Diffuse microvesicular steatosis: Symptoms: often severely ill (in ICU) Liver chemistry tests: mild elevations of AST & ALT Histologic features: diffuse microvescular steatosis; no inflammation; no hepatocyte necrosis or dropout; no fibrosis

• Drugs & toxins • Mimics: • Alcoholic foamy degeneration – • Acute fatty liver of pregnancy – Diabetic (glycogenic) • Inherited disorders of fatty acid hepatopathy beta-oxidation • Inherited urea cycle disorders • Mitochondrial cytopathies • Wolman disease • Cholesterol ester storage disease •

Macrovesicular Microvesicular H&E Stain Oil Red O Stain Pessayre D et al. Mitochondrial involvement in drug-induced liver injury. Handb Exp Pharmacol 2010; 196:311-65. Begriche K et al. J Hepatol 2011; 54:773–94. 14-18236 Clinical History

• 7 year old female with lissencephaly and disorder presents with respiratory distress • Started on cefpodoxime / azithromycin • TB = 0.7, AST = 301, ALT = 116, alk phos = 153; INR = 1.2 • Abdominal U/S: mild hepatomegaly • Lactate = 5.0: – Causing metabolic acidosis – Thought to be cause of increased work of breathing • TB = 0.6, AST = 402, ALT = 123, alk phos = 131; INR = 1.5

• Liver biopsy performed

Additional Clinical Information

• Meds: – Levetiracetam – Phenobarbital (recently added) – Topiramate – Valproic acid

Acute Fatty Liver with Lactic Acidosis and Hepatic Dysfunction

Criteria for Diagnosis Medications • Increased serum lactate • I.V. tetracycline • Microvesicular steatosis • Linezolid • Increased AST/ALT • Fialuridine • Decreased albumin • Didanosine • Prolongation of PT • Zidovudine • Increased ammonia • Stavudine • Salicylate • r/o metabolic disorder • Valproic acid

David E Kleiner http://livertox.nih.gov/Phenotypes_lact.html

Clinical Follow-up

• Add clobazam (onfi) and taper valproic acid • Carnitine and thiamine administered

• Discharged with improved seizure control and falling liver chemistry tests

13-3850 Clinical History • 4 month old F admitted for new onset of • Patient born "2 weeks early" via C-section for oligohydramnios and breech position (5lb 1 oz) • In retrospect “always a little sallow”, but no clay colored stools or dark urine • PE: scleral icterus, cushingoid facies, hepatomegaly • Hypoketotic hypoglycemia & anion gap metabolic acidosis • Tachypnea (RR = 36/min) • TB = 12.9, DB = 9.8 in ER • TB = 13.8, AST = 184, ALT = 123, alk phos = 842

Clinical Follow-up Episodes of Hypoglycemia in the Hospital • Pyruvic acid - normal • Alpha-1-AT phenotype - normal • Lactate - normal • Peroxisomal panel - normal • Serum amino acids – elevated methionine • GAL-1-P Uridyltransferase - normal • Urine organic acids – normal • Acyl carnitine profile - abnormal

Laboratory Follow-up

• Acylcarnitine = 0.86 (2 to 27.7 nmol/mL) • Total carnitine = 83 (38 to 68 nmol/mL) • Free carnitine = 76 (27 to 49 nmol/mL) • AC/FC Ratio = 0.01 (0.2 to 0.5)

In the setting of hypoketotic hypoglycemia and liver dysfunction, the most likely etiology is carnitine palmitoyltransferase IA deficiency • The carnitine palmitoyltransferase 1A (CPT1A) gene is located on chromosome 11q • CPT1A is produced in the liver and is essential for fatty acid oxidation by mitochondria • CPTA1 binds carnitine to long chain fatty acids LCFAs so they can cross the inner membrane of mitochondria • Once LCFAs are inside mitochondria, carnitine is removed and they can be metabolized to produce ATP • During periods of fasting LCFAs are an important energy source for the liver and other tissues Acute Fatty Liver of Pregnancy (AFLP)

• Presents in third trimester with malaise, N&V, • Laboratory evaluation: – Hypoglycemia – Increased TB (10mg/dL) & AST/ALT (200-300 U/L) – Hypocholesterolemia & hypotriglyceridemia • Diffuse hepatic microvesicular steatosis • Treated by prompt delivery Acute Fatty Liver of Pregnancy Acute Fatty Liver of Pregnancy 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHAD)

• Autosomal recessive disorder of mitochondrial fatty acid beta-oxidation • Causes life threatening hypoketotic hypoglycemia in infants • Produces microvesicular steatosis in the infant’s liver • Confusion with Reye syndrome LCHAD (& CPTA1) in AFLP

• AFLP develops in 30% of mothers who deliver an infant with LCHAD def. • No risk of AFLP in the same mothers who deliver an infant without LCHAD def. • Maternal disease due to generation of toxic 3- hydroxy-fatty acid metabolites by the LCHAD deficient infants (?) • Most mothers with AFLP give birth to healthy infants and are not heterozygotes for LCHAD def. • Other disorders of fatty acid [MCAD, VLCAD, SCAD] can produce macro- or microvesicular steatosis in infants (and adults) Medium chain 3-hydroxyacyl-CoA dehydrogenase deficiency Reye Syndrome

• Visceral microvesicular steatosis and cerebral edema • Association with aspirin use and viral prodromal syndrome; incidence is falling greatly worldwide • Pathologic Features: – Microvesicular steatosis – Minimal , hepatocyte necrosis, lobular inflammation in some cases – EM reveals characteristic mitochondrial abnormalities • Many cases are probably actually due to MCAD or other fatty acid beta-oxidation disorders • Combination of heterozygosity for MCAD, salicylate toxicity and viral illness may underlie some cases

Orlowski JP. Crit Care Med 1999; 27:1582-87. Reye Syndrome

Sarnaik AP. Crit Care Med 1999; 27:1674-6. Reye Syndrome August 15, 1995 Anita Srikameswaran and Louise Kiernan 11

At 6 feet 2 inches, 230 pounds and an outstanding offensive lineman for one of the area's most competitive high school football teams, ##### ####### may have appeared invulnerable to the heat.

But on Monday, three days after he collapsed during football practice in 95-degree weather, the 17-year-old Mt. Carmel High School senior received a liver transplant that almost certainly saved him from imminent death.

When he arrived at the hospital, #######’s body temperature was 106 degrees. His high body temperature caused his muscles to break down, releasing harmful proteins into his bloodstream and threatening his vital organs. By Sunday afternoon, #######’s liver stopped working, and he was placed on the transplant list by 8 p.m. In an extraordinary stroke of luck, a liver was found by 2 a.m.

95-10778 Heat Stroke

Berger J, Hart J, Millis M. Fulminant hepatic failure from heat stroke. J Clin Gastroenterol 2000: 30:429-31.

C13-8478 Clinical History Case Courtesy of Gerson Paull Rockdale Medical Center, Conyers, GA

• 43 y.o. M with a 7 day history of jaundice • Prior admissions for alcoholic • Denies current alcohol use • TN = 13. 8, AST = 128, ALT = 45, alk phos = 529 • Albumin = 2.0, PT = 17.9, PTT = 39.6, INR = 1.3 • U/S and CT scan: – Chronic but no – No dilatation of extrahepatic biliary tree

Alcoholic foamy degeneration

S10-21430 Clinical History

• 28 y.o. F with history of IDDM presents with abdominal pain and distension • s/p traffic accident with traumatic brain injury; maintained on Tegretol • Admitted for previous similar episode two months ago • CT scan revealed hepatomegaly • TB = 0.4, AST = 1481, ALT = 766, alk phos = 256 • HAV, HBV, HCV all negative • Serum ANA, anti-SMA negative • Ceruloplasmin and alpha-1-antitrypsin levels normal • Urine toxicology screen negative

PAS stain S10-21430 Follow-up

• Hemoglobin A1C = 11.8% (3.9 – 6.1%)

Literature Citations

• Bronstein HD et al. Marked enlargement of the liver and transient ascites associated with the treatment of diabetic acidosis. N Engl J Med 1959; 261:1314-18.

• Lorenz G, Barenwald G. Histologic and electron microscopic liver changes in diabetic children. Acta Hepatogastroenterol 1979; 26:435-8.

• Van Steenbergen W, Lanckmans S. Liver disturbances in obesity and mellitus. Int J Obes Relat Metab Disord 1995; 19:S 27-36.

• Chatila R et al. Hepatomegaly and abnormal liver tests due to glycogenosis in adults with diabetes. 1996; 75:327-33.

• Ledesma S et al. Hepatic dysfunction caused by the accumulation of hepatocellular glycogen in diabetes mellitus. J Gastroenterol Hepatol 2000; 23:456-57.

15-2901 Clinical History • 1 y.o. M seen for protuberant abdomen and sleeping too much – pediatrician reassures Mom • Breast fed for 6 mos. and then switched to Enfamil • Developed abd distention with spitting up episodes • Switched to Gentlease and then soy based formula without improvement • Seen by pediatrician again – CT scan reveals hepatomegaly • Weight = 9.0 kg (23rd percentile) • Height = 66 cm (26th percentile) • TB = 0.2, AST = 578, ALT = 660, alk phos = 314

Glycogen Storage Disease Type I glucose-6-phosphatase

• Clinical features: – Short stature and hepatomegaly – Profound fasting hypoglycemia – Lactic acidosis and – Renal disease later in life (Fanconi’s) – Neutropenia with infections & IBD-like in type Ib • Pathologic features: – Marked glycogen deposition producing cobblestone appearance – Glycogenated hepatocyte nuclei – Mild to moderate macrovesicular steatosis – Mild portal fibrosis, but not cirrhosis Glycogen Storage Hepatic Predominant (Important) Types • Type I: – Von Gierke’s disease – Glucose-6-phosphatase (type Ia) – 17q21 – Glucose-6-phosphatase transporter (type Ib) – 11q23.3 • Type III: – Cori’s disease (Forbes’ disease) – 1p21 – Amylo-1,6-glucosidase (debrancher enzyme) • Type IV: – Andersen’s disease (amylopectinosis) - 3p12 – Amylo-(1,4→1,6)-transglycosylase (brancher enzyme) • Types VI and IX: – Hers’ disease – Liver phosphorylase (type VI) – Phosphorylase kinase (type IX) Glycogen Storage Disease Type III amylo-1,6-glucosidase (debrancher) • Clinical features: – Short stature and hepatomegaly – Cardiomyopathy & progressive muscle weakness in adulthood; no renal disease – Mild fasting hypoglycemia • Pathologic features: – Marked glycogen deposition producing cobblestone appearance – Glycogenated hepatocyte nuclei – Minimal macrovesicular steatosis – Cirrhosis in adulthood in some patients 02-14478 Clinical History

• 39 year old male with hepatomegaly and congestive heart failure • CT scan: hepatomegaly but no focal lesion • Needle biopsy of the liver

Glycogen Storage Disease Type III Glycogen Storage Disease Type III

Heart Glycogen Storage Disease Type IV Brancher enzyme • Clinical Features: – Rare disorder, less than 50 cases reported – Hepatosplenomegaly, failure to thrive, congestive heart failure – Cirrhosis by age of 2 years – Abnormal neuromuscular development in 50% • Pathologic features: – Micronodular cirrhosis – Amylopectin-like deposits within hepatocytes – Deposits are PAS +, AB +, colloidal iron + – Deposits composed of fibrillary material by EM – Diff Dx: Lafora’s disease (myoclonus) C03-9883 Clinical History

• 14 month old M presents with hepatomegaly and congestive heart failure • Mildly increased LCTs • Liver biopsy performed

Glycogen Storage Disease Type IV

C O L L O I D A L

I R O N

S T A I N Glycogen Storage Disease Types VI and IX • Clinical features: – May experience mild hypoglycemia in infancy – Hepatomegaly as a child or adult – Mild liver chemistry abnormalities • Pathologic features: – Marked hepatocyte glycogen deposition producing cobblestone appearance – Glycogenated hepatocyte nuclei – Very little (no) steatosis – Mild portal fibrosis (if any) Glycogen Storage Disease Type VI Glycogen Storage Disease Type VI Microvesicular Diabetic Glycogen Steatosis Hepatopathy Storage Disease Take Home Points • Cholesterol ester storage disease is under- recognized by liver pathologists • Common causes of diffuse microvesicular steatosis include drugs and rare metabolic diseases • Diffuse microvesicular steatosis is usually a result of severe mitochondrial injury • Most patients with diffuse microvesicular steatosis are severely ill, although serum AST/ALT levels are low • Mimics of diffuse microvesicular steatosis include diabetic hepatopathy & glycogen storage disease MICROVESICULAR STEATOSIS John Hart, M.D. [email protected]

INTRODUCTION

Diffuse microvesicular steatosis is a much rarer pathologic change than macrovesicular steatosis, and its presence is usually a sign of severe metabolic derangement, most often as a result of mitochondrial dysfunction. The mitochondrial injury leads to failure of hepatic fatty acid beta-oxidation (FAO), which is the primary source of energy for skeletal muscle and the heart. Hepatic FAO also drives gluconeogenesis and the synthesis of ketone bodies, which are critical for brain function when blood glucose levels are low. Therefore, diseases that cause diffuse hepatic microvasculars steatosis will result in lactic acidosis and hypoglycemia. If left untreated, the patient can develop progressive hyperammonemia, coagulopathy, coma and . This dramatic clinical course unfolds despite the fact that the serum AST and ALT levels are generally only mildly elevated and no or minimal hepatocyte necrosis is evident microscopically. Owing to their relative small muscle mass and high energy needs infants are particularly susceptible to the deleterious effects of impaired FAO. There are numerous enzymatic steps in the pathway of hepatic mitochondrial FAO and therefore there are a number of genetic diseases and drugs that can produce diffuse microvesicular steatosis. Heat stroke also causes mitochondrial dysfunction which can result in diffuse microvesicular steatosis and liver failure.

In microvesicular steatosis the lipid droplets can be quite small and the hepatocyte nucleus remains in the normal central position, which can make histologic recognition problematic. Confirmation with an Oil Red O or Sudan Black stain (or by electron microscopy) provides reassurance that this significant diagnosis is in fact correct. The most common toxic insults, metabolic disorders, and drugs that can lead to the development of diffused microvesicular steatosis are outlined in the following discussion.

ACUTE FATTY LIVER OF PREGNANCY, HELLP SYNDROME, AND INBORN ERRORS OF FATTY ACID BETA-OXIDATION

The relationship between acute fatty liver of pregnancy (AFLP) and HEELP syndrome, if any, is a matter of current controversy. Both conditions develop during the third trimester of pregnancy and both are best treated by prompt delivery. There are, however, a number of clinical and histologic features that separate these two entities, leading some investigators to conclude that they arise via different pathogenic mechanisms. Diffuse microvesicular steatosis is the defining feature of AFLP. Patients most often present with malaise, and vomiting and abdominal pain. Laboratory evaluation usually reveals significant hypoglycemia, elevated TB (10 mg/dL) and AST/ALT (300-400 IU/L), hypocholesterolemia and hypotriglyceridemia. In contrast, patients with HELLP syndrome present with headache, hypertension, and proteinuria (preeclampsia), and their levels of TB, AST/ALT are usually lower. In addition patients with HEELP syndrome exhibit hemolysis and thrombocytopenia, which are considered defining features. Liver biopsies in patients with HELLP syndrome reveal focal clusters of necrotic hepatocytes and hemorrhage and fibrin deposition. Microvesicular steatosis has been reported in some cases of apparent HELLP syndrome, which is one reason that some investigators considered AFLP and HELLP to be two ends of the spectrum of the same underlying disorder.

Recently molecular techniques have demonstrated that many women who delivered children with long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency were at a high risk of development of either AFLP or HELLP. This autosomal recessive disorder of mitochondrial fatty acid beta-oxidation in neonates produces a life threatening disorder characterized by severe hypoketotic hypoglycemia, cardiomyopathy, and . The liver of an affected infant reveals marked microvesicular steatosis. Some past cases of so-called “sudden infant death syndrome” (SIDS) were probably a result of LCHAD or other genetic defects of fatty acid beta-oxidation. A recent study revealed that AFLP or HELLP occurred in the mother in 31% of pregnancies in which an LCHAD deficient infant was delivered, but never in these same mothers when they delivered an unaffected child. These mothers are, of course, obligate heterozygotes for an LCHAD mutation. The pathogenic mechanisms which explain why the risk of development of AFLP or HELLP in these women is limited to pregnancies involving LCHAD deficient infants is unclear, but may be related to the generation of toxic 3-hydroxy-fatty acid metabolites by the LCHAD deficient fetus. Moreover, there are data that suggest that fatty acid oxidation by mothers is reduced by 25-50% in late gestation. Still, most women with AFLP or HELLP give birth to healthy infants and are not heterozygotes for LCHAD deficiency, and therefore other pathogenic mechanisms (? other fatty acid beta- oxidation defects) must be involved. For instance, maternal illness during pregnancy with a carnitine palmitoyltransferase IA deficient fetus has been reported. The other 3- hydroxyacyl-CoA dehydrogenase enzymes involved in fatty acid oxidation [medium chain (MCAD), very long chain (VLCAD), short chain (SCAD)] have also been shown to produce similar syndromes in infants (and adults), with either macro- or microvesicular steatosis (although they have not been reported to produce AFLP or HEELP).

REYE SYNDROME

Since the recognition of the epidemiological link between the use of aspirin for a viral illness in children and the subsequent development of Reye syndrome (microvesicular steatosis and cerebral edema, the disorder has become vanishingly rare. A variety of viral illnesses have been associated with Reye's syndrome, including influenza B and varicella. Atypical cases of Reye's syndrome, particularly those in children less than 2 years old, or with a familial history, were probably actually due to genetic defects in the genes for the enzymes involved in fatty acid beta-oxidation (see discussion above). In fact, a study that investigated patients diagnosed with Reye's syndrome who survived their illness revealed that 69% actually had other diseases, most commonly inborn errors of metabolism (60%). The most common genetic defect was medium chain 3-hydroxyacyl-CoA dehydrogenase (MCAD) deficiency, but there were a large number of other disorders also implicated. Salicylates in high doses have been reported to cause microvesicular steatosis, and it is intriguing to speculate whether patients with classic Reye's syndrome may have been heterozygotes for one of these same genetic disorders.

The large number of disorders that can produce a "Reye-like" syndrome is undoubtedly responsible for minor variations in the reported histologic changes in the liver. Most studies report pure diffuse microvesicular steatosis, but mild cholestasis, necrosis or inflammation has been noted in occasional cases. Electron microscopic examination has demonstrated mitochondrial abnormalities said to be characteristic.

DRUG INDUCED DIFFUSE MICROVESICULAR STEATOSIS

Drugs are an important cause of microvesicular steatosis, with valproic acid, salicylates, and intravenous high dose tetracycline being the most commonly reported in the past. More recently, nucleoside reverse transcriptase inhibitors (e.g., zidovudine, stavudine didanosine, fialuridine ) used in the treatment of HIV and other viral infections have also been reported to produce this form of hepatic injury. The common link between this wide range of drugs is hepatic mitochondrial injury. For the newer drugs several months may pass before clinically evident liver dysfunction is evident. These drugs produce diffuse microvesicular steatosis without significant hepatocyte necrosis or inflammatory cell infiltrates.

MIMICS OF DIFFUSE MICROVESICULAR STEATOSIS

Diabetic (glycogenic) hepatopathy can occur as a result of poor glycemic control in patients with insulin dependent diabetes mellitus. The derangement of normal hepatic glucose metabolism leads to marked glycogen accumulation in hepatocytes, which can manifest clinically as significant hepatomegaly and abdominal pain. Serum AST and ALT levels are generally mildly elevated, but in some cases can rise to greater than 1000 IU/L. Liver biopsies generally reveal diffuse hepatocyte swelling due to glycogen accumulation, as well as minimal inflammation and macrovesicular steatosis. As the hepatocyte nuclei remain centrally placed, the appearance can resemble microvesicular steatosis. However, a PAS stain will reveal strong diffuse hepatocyte cytoplasmic staining in diabetic hepatopathy, compared to apparent decreased staining (compared to normal liver) in microvesicular steatosis.

Glycogen storage diseases can also mimic microvesicular steatosis both clinically and histologically. There are approximately a dozen well defined clinical disease states caused by genetic defects in the pathway of glycogen metabolism, but only five (types 1, 3, 4, 6 and 9) primarily affect the liver and produce histologic hepatic manifestations. In this subset of disorders, all but one of which is transmitted in autosomal recessive fashion, patients generally present with hepatomegaly and are at risk for severe hypoglycemia. Extrahepatic manifestations due to glycogen accumulation in other organs occur in some of the disorders. A liver biopsy is often performed to document abnormal glycogen deposition and to exclude other disease states. In most cases a snap frozen portion of the biopsy can be utilized for determination of the activity of the particular enzyme thought to be affected in an individual patient. Molecular diagnostic testing is possible from the biopsy sample, or from DNA extracted from a skin biopsy or whole blood sample.

Glycogen storage disease type 1 usually presents in the neonatal period or in infancy with marked hepatomegaly and hypoglycemic episodes. Untreated children may develop failure to thrive, growth retardation, delayed puberty, and short stature. Patients that survive into adulthood are at risk for the development of hepatic adenomas and . The genetic defect responsible for type 1a occurs in the G6PC gene on chromosome 17q21, which codes for glucose-6-phosphatase. In glycogen storage disease type Ib mutations of the SLC374A gene located on chromosome 11q23 lead to decreased activity of the glucose-6-phosphatase translocase enzyme. This defect also causes neutropenia and impairs neutrophil function, resulting in recurrent bacterial infections and gastrointestinal inflammation and ulceration. Liver biopsy specimens in both type 1a and 1b reveal diffuse hepatocyte swelling due to excess accumulation of glycogen, nuclear “hyperglycogenation”, macrovesicular steatosis, and in some case mild portal fibrosis.

Glycogen storage disease type 3 is caused by mutation in the AGL gene located on chromosome 1p21, which encodes the glycogen debrancher enzyme. In about 15% of affected patients abnormal glycogen accumulation is limited to the liver, while in 85% of patients there is involvement of both liver and skeletal muscle (and in cardiac myocytes in some). Differential transcription and alternative exon usage account for the distinct isoforms of the enzyme that are expressed in a tissue specific fashion. The disease manifests during the first year of life, with fasting hypoglycemia, marked hepatomegaly, short stature, and in some patients, progressive myopathy and cardiomyopathy. Liver biopsy specimens reveal excess glycogen in hepatocytes and varying degrees of portal fibrosis, but minimal steatosis. Hepatocellular carcinoma has been reported in patients with cirrhosis.

Glycogen storage disease type 4 is the rarest form of glycogen storage disease involving the liver, and is quite clinically heterogenous. In many patients skeletal or cardiac muscle involvement dominates the clinical picture, but severe hepatic involvement is also common and cirrhosis may develop in early childhood. The disease is caused by deficient branching enzyme activity. Liver biopsies reveal distinctive cytoplasmic deposits of amylopectin-like material, which can be highlighted by a colloidal iron stain.

Glycogen storage disease type 6 is clinically much milder and usually presents in adulthood with hepatomegaly and mild to moderate hypoglycemic episodes. Confusion with diabetic hepatopathy may occur since this disorder produces similar clinical and histologic findings. Liver biopsies demonstrate excessive hepatocellular glycogen but no steatosis or fibrosis.

Glycogen storage disease type 9 is also relatively clinically benign, and develops as a result of decreased phosphorylase kinase activity due to mutations in any of several genes that code for the subunits of the enzyme. Mutations in the PHKB gene on chromosome 16q12-13 or the PHKG2 gene on chromosome 16p11-12, which encode for the alpha and gamma subunits respectively, result in a similar clinical phenotype characterized by mild hepatomegaly, fasting hyperketosis, and growth retardation, which often subside as the patient reaches adulthood. The only X-linked glycogen storage disease, due to alteration in the alpha subunit of the phosphorylase kinase protein, is caused by mutations in the PHKA2 gene on chromosome Xp22.2-1. This disorder is phenotypically similar to the other forms of glycogen storage disease type 9.

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Drug Induced Microvesicular Steatosis

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