Clinical features

Hereditary hemochromatosis (HH) is a group of inherited disorder that results in excess iron storage. HH is the most common genetic disorder in whites, with a prevalence of approximately 1 in 200. Up to 85% of clinically recognized cases in patients of northern and western European origin are homozygotes for the C282Y mutation, but this mutation is rare in southern European populations and is not found in African and Asian populations. The distribution of the mutation suggests a Celtic origin, and a competitive advantage for heterozygotes by making iron deficiency less likely is postulated.

Several forms of the disease are recognized: HFE hemochromatosis accounts for more than 90% of cases. Three HFE mutations are described; the most common is a missense mutation designated C282Y, which prevents formation of a disulfide bond necessary for binding of HFE protein to β ₂ -microglobulin. Other less common mutations are designated H63D and S65C. Juvenile hemochromatosis is caused by mutations of the hemojuvelin (HJV) and hepcidin antimicrobial peptide (HAMP) genes. Transferrin receptor 2 (TFR2) hemochromatosis is related to TFR2 gene mutations, and type B ferroportin disease is caused by SLC40A1 mutation of the membrane iron-regulated transporter ferroportin. All forms of the disease are transmitted as an autosomal recessive disorder, except the type B ferroportin disease, which has an autosomal dominant inheritance. Hepcidin, a peptide hormone encoded by the HAMP gene in hepatocytes, plays a central role in iron metabolism, analogous to that of insulin in glucose metabolism. All currently known forms of HH are due to an abnormal production, regulation, or activity of hepcidin.

Clinical manifestations of HH are varied. The process of iron accumulation to toxic levels may take decades, with most patients presenting between ages 40 and 60 years. Clinical manifestations occur earlier in juvenile hemochromatosis. Women present later than men beause of the protective effects of menstruation. Common presenting symptoms are lethargy, hepatomegaly, arthropathy, hypogonadism, abdominal pain, and skin pigmentation. Cardiac failure may occur due to iron deposition in myocardial fibers. Diabetes mellitus and cirrhosis are late manifestations. Endocrine gland compromise is typically the predominant clinical manifestation in juvenile hemochromatosis, although hepatic iron overload also occurs.

Radiologic features

Severe iron overload can be detected by computed tomography scan and magnetic resonance imaging. The latter is considered more accurate in estimating hepatic iron stores.

Pathologic features

Gross findings

In early stages of HH, the liver may appear grossly normal or slightly darker in color. As iron accumulates, the liver and other organs such as the pancreas become rust colored. Cirrhosis due to HH is initially micronodular, evolving into macronodular cirrhosis ( Fig. 18-1 ). Nodules of hepatocellular carcinoma often contain less iron and so appear lighter than cirrhotic nodules.

Cirrhosis due to hereditary hemochromatosis is initially micronodular. The liver is rust colored because of accumulation of excess iron. Note nodule of hepatocellular carcinoma ( arrow ).

Microscopic findings

Iron deposits in HH first appear in periportal hepatocytes as finely granular yellow-brown pigment most easily recognized on iron stain and concentrated in a pericanalicular location in the cell. No increase in fibrosis is seen in early stages, and there is little or no inflammation. As iron continues to accumulate, the deposits become coarser, and while the periportal accentuation is maintained ( Fig. 18-2 A), hepatocytes throughout the lobule exhibit excess iron stores. Hemosiderin granules are also seen in Kupffer cells and bile duct epithelial cells in these later stages. Fibrosis is initially periportal, and expands to form portal-portal bridging septa and cirrhotic nodules with disease progression.

A, In hereditary hemochromatosis, iron accumulates in hepatocytes before spilling over to Kupffer cells. The iron deposition is in a zonal distribution, with accumulation predominantly in periportal hepatocytes in early stages of the disease. B, Prussian blue stain for iron is helpful in highlighting the zone 1 distribution in HH. C, In late stages of secondary hemochromatosis due to iron overload, heavy iron deposition may be seen in both Kupffer cells ( arrow ) and hepatocytes.

HEREDITARY HEMOCHROMATOSIS—PATHOLOGIC FEATURES

Gross findings

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  Early cirrhosis is micronodular, evolving into macronodular cirrhosis

  
  
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  Deposition of iron in liver results in rusty color

  
  
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  Pancreas, spleen, and other organs are similarly discolored

Microscopic findings

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  Deposition of iron in periportal hepatocytes, with later accumulation in zone 2 and zone 3 hepatocytes

  
  
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  Lesser degree of iron deposition in Kupffer cells

  
  
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  Periportal and bridging fibrosis progress to cirrhosis

Ultrastructural findings

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  Ferritin and hemosiderin accumulate within secondary lysosomes (siderosomes)

Genetics

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  Autosomal recessive inheritance (except juvenile hemochromatosis—autosomal dominant)

  
  
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  Approximately 80% of HH is due to single G to A mutation at position 282 of HFE gene (C282Y)

  
  
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  Non-C282Y mutations result in less severe iron overload, and clinical manifestation of disease does not occur

  
  
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  Non-HFE HH include juvenile hemochromatosis ( HJV and HAMP gene mutations), transferrin receptor 2 hemochromatosis ( TRF2 gene mutations), and type B ferroportin disease ( SLC40A1 mutation)

Differential diagnosis

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  Secondary iron overload

  
  
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  Hemolytic anemias and other hematologic disorders

  
  
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  Blood transfusions

  
  
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  Hemosiderosis in alcoholic liver disease, hepatitis C, hemodialysis, and metabolic syndrome

Ancillary studies

Special stains for iron such as Prussian blue stain are helpful in confirming accumulation of iron in hepatocytes (see Fig. 18-2 B) and differentiation of iron from other brown pigments such as bile and lipofuscin. Immunohistochemistry and electron microscopy are not useful.

Differential diagnosis

HH must be distinguished from secondary iron overload seen most commonly in various forms of chronic anemia such as sickle cell disease and in hepatic siderosis associated with alcoholic liver disease. Whereas iron accumulation in hepatocytes as compared with Kupffer cells is more pronounced in HH, considerable overlap in the pathologic features is seen with secondary hemochromatosis, and quantitative iron determination by chemical techniques or atomic absorption spectrophotometry is more accurate. The hepatic iron index, obtained by dividing the weight of iron in the biopsy by the patient’s age, is usually greater than 1.9 in patients with HH but less than 1.9 in heterozygotes and in patients with alcoholic siderosis. HH due to common HFE gene mutations can be established easily using polymerase chain reaction–based techniques.

Prognosis and therapy

Prognosis is related to the presence of organ damage, which correlates with severity of iron overload. Patients without cirrhosis or diabetes who undergo treatment have survivals similar to those of age- and sex-matched normal subjects. The 10-year survival rate in cirrhotic patients who undergo treatment is roughly 70%; hepatocellular carcinoma is an important late complication and may occur years after iron depletion.

Treatment is aimed at reducing iron burden; the most commonly used strategy is phlebotomy at regular intervals until the serum ferritin level falls below 50 ng/mL. Iron chelation agents are not often used to treat HH but are more commonly used to treat secondary iron overload, for which phlebotomy may not be a practical option.

Clinical features

Secondary iron overload is most commonly associated with chronic anemias such thalassemia, sideroblastic anemia, anemias associated with defective heme synthesis, and sickle cell disease. Other causes include transfusion-related iron overload in aplastic anemia, hemosiderosis associated with alcoholic liver disease, hemodialysis, hepatitis C, porphyrias, and nonalcoholic fatty liver disease/metabolic syndrome. Dietary iron overload (Bantu siderosis or African iron overload) in sub-Saharan Africans is related to consumption of home-brewed alcohol; recent studies suggest a non-C282Y genetic influence in this population. As in HH, many forms of acquired iron-overload syndromes are now believed to be related to downregulation of hepcidin. Clinical features in secondary iron overload vary according to disease severity but may be similar to those of HH.

Pathologic features

Differential diagnosis

Heavy deposition in iron in Kupffer cells as compared with hepatocytes favors secondary hemochromatosis over HH. Clinical history is usually helpful, but genetic testing for HFE mutations and quantitative iron determination may be necessary.

Prognosis and therapy

Therapy in secondary iron load is aimed at treating the underlying disease. Iron chelation therapy is the only effective treatment for iron overload due to refractory anemias. Prognosis is usually related to the underlying disease.

Clinical features

Wilson’s disease is an autosomal recessive disorder of copper metabolism; the defect has been identified as mutation in a cation-transporting ATPase ATP7B, the protein responsible for transporting copper into hepatocyte secretory pathways for excretion into bile. A large number of different mutations, mostly missense mutations, have been identified. The majority of affected individuals are compound heterozygotes; no consistent correlation between genotype and clinical manifestations has been observed. Elevated copper is believed to induce cell damage by stimulating the production of reactive oxygen species.

Most patients with Wilson’s disease present with hepatic or neuropsychiatric manifestations, due to accumulation of copper to toxic levels in liver or basal ganglia, respectively. Presentation with hepatic disease is most common in children 10 to 13 years of age but may be seen late in life. Serum transaminase levels are commonly elevated, and patients may present with cirrhosis. Some patients present with massive hepatic necrosis and fulminant liver failure, usually accompanied by hemolytic anemia due to abrupt release of massive amounts of copper from the liver. Initial presentation with neurologic symptoms, most commonly parkinsonian symptoms, occurs roughly 10 years later than presentation with hepatic findings. Kayser-Fleischer rings are due to the deposition of copper in the limbus of the cornea and may be detected on slit-lamp examination.

Laboratory findings in Wilson’s disease include low serum ceruloplasmin and elevated urinary copper concentrations. Hepatic copper concentration is elevated (more than 250 μg/g dry weight).

Pathologic features

Gross findings

The liver may be grossly normal or mildly steatotic in early stages of Wilson’s disease. In later stages, progressive fibrosis leads to predominantly macronodular cirrhosis ( Fig. 18-3 ).

Cirrhosis due to Wilson’s disease is coarsely macronodular with variation in nodule size.

Microscopic findings

Morphologic changes in early Wilson’s disease may be mild ( Fig. 18-4 A), and a high index of suspicion is needed on the part of the pathologist. Mild to moderate steatosis is common and may be microvesicular or macrovesicular. Glycogenated nuclei (see Fig. 18-4 B) are also found. A mild chronic hepatitis pattern of injury with increased lymphocytes in portal tracts and spotty hepatocyte necrosis is relatively common. Mallory’s hyaline may also be seen in Wilson’s disease. As the disease progresses, periportal fibrosis (see Fig. 18-4 C) progresses to bridging fibrosis and cirrhosis. Copper is not visible on routine hematoxylin and eosin stains but may be visualized with special stains such as rhodanine or rubeanic acid. Victoria blue or Shikata stains such as orcein and aldehyde fuchsin stain copper binding protein and may show a granular cytoplasmic pattern of staining in hepatocytes. Distribution of copper within the liver is irregular, especially in cirrhotic nodules. Copper and copper binding protein may be found in Kupffer cells in patients presenting with fulminant liver failure (see Fig. 18-4 D).

A, Early-stage Wilson’s disease often shows a nonspecific chronic hepatitis pattern of injury, with portal chronic inflammation and focal interface hepatitis. B, Glycogenated nuclei are a common but nonspecific finding in Wilson’s disease. C, In more advanced disease, extensive fibrosis and chronic inflammation is seen and hepatocytes may show ballooning degeneration. D, Victoria blue stain ( shown ) and Shikata stains highlight increased copper binding protein in Wilson’s disease. In this case of fulminant liver failure, copper binding protein was present in both hepatocytes and Kupffer cells.

WILSON’S DISEASE—PATHOLOGIC FEATURES

Gross findings

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  Early: liver may be grossly normal or mildly enlarged

  
  
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  Massive hepatic necrosis in some cases

  
  
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  Late: macronodular cirrhosis

Microscopic findings

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  Early: nonspecific chronic hepatitis pattern of injury

  
  
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  Glycogen nuclei in hepatocytes and steatosis are common

  
  
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  Mallory’s hyaline may be seen

  
  
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  Progressive hepatocyte necrosis and fibrosis lead to cirrhosis

  
  
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  Copper accumulation in liver, primarily in hepatocyte cytoplasm, may be visualized with special stains (rhodanine, rubeanic acid)

Ultrastructural findings

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  Mitochondrial changes include heterogeneity in size and shape, increased matrix density, and crystalline inclusions

  
  
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  Increase in peroxisomes and lipofuscin granules

Genetics

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  Autosomal recessive disorder

  
  
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  ATP7B gene on 13q14.3 is mutated

  
  
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  Numerous mutations reported

  
  
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  Gene product transports copper across hepatocyte membrane into bile canaliculus

Differential diagnosis

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  Chronic viral hepatitis

  
  
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  Autoimmune hepatitis

  
  
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  Nonalcoholic fatty liver disease

  
  
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  Pathologic findings are relatively nonspecific

Differential diagnosis

The histologic differential diagnosis of Wilson’s disease depends on the pattern of injury manifested in the liver biopsy. Other common causes of a chronic hepatitis pattern of injury in young patients include chronic viral hepatitis and autoimmune hepatitis and must be excluded by appropriate clinical testing. The combination of low serum ceruloplasmin and high urinary copper excretion should suggest Wilson’s disease. The diagnosis is usually confirmed by quantitative copper analysis of hepatic tissue. Other childhood syndromes associated with increased hepatic copper content include Indian childhood cirrhosis, which has been linked to consumption of foods cooked in copper pots. It most likely has a genetic component and is seen only in India. Similar rare disorders include idiopathic copper toxicosis, endemic Tyrolean cirrhosis, and non-Indian childhood cirrhosis.

Prognosis and therapy

The copper-chelating agent d -penicillamine, accompanied by dietary restriction of copper, is the treatment of choice and in most cases halts disease progression. Patients with fulminant hepatic failure or decompensated cirrhosis are candidates for hepatic transplantation.

Prognosis depends on compliance with therapy and with stage of disease at diagnosis. Rarely, hepatocellular carcinoma occurs in the setting of cirrhosis in Wilson’s disease. Hepatic onset may be associated with a poorer prognosis.

Clinical features

α ₁ -Antitrypsin (α ₁ AT), a plasma serine protease inhibitor, plays a key role in controlling tissue degradation by complexing with proteases, such as elastase, trypsin, chymotrypsin, and thrombin. This function is particularly critical in the lung, where α ₁ AT inhibits leukocyte elastase and prevents degradation of alveolar walls by this enzyme. More than 100 genetic variants of α ₁ AT have been identified; most are associated with normal levels and function of the protein. The deficiency state is most commonly caused by homozygosity for the PI*Z allele, in which alanine is substituted for leucine at amino acid 213, causing self-aggregation of the protein, which is trapped within the endoplasmic reticulum of hepatocytes. The PI*Z protein migrates more slowly on isoelectric focusing than the normal PI*M protein.

The most common clinical disorder associated with α ₁ AT deficiency is pulmonary disease, specifically emphysema, which preferentially affects basal regions of the lung. Roughly 17% of patients with α ₁ AT present with liver disease in infancy, manifested as neonatal cholestasis, with 25% of these patients developing cirrhosis in childhood. Liver disease associated with α ₁ AT deficiency may be clinically silent in early life and present in late adulthood as cirrhosis, usually in male patients.

Pathologic features

Microscopic findings

The most characteristic histologic feature of α ₁ AT is the presence of globular eosinophilic period acid-Schiff (PAS)-positive, diastase-resistant cytoplasmic inclusions found predominantly in periportal hepatocytes ( Fig. 18-5 A and B). The inclusions are variable in size, increasing in number and size with age, and may be inconspicuous in biopsy samples from children. In infants presenting with cholestatic liver disease, morphologic changes of neonatal hepatitis such as canalicular cholestasis, giant cell transformation of hepatocytes, and hepatocyte ballooning degeneration (see Fig. 18-5 C) are seen. In these cases, interlobular bile ducts may be reduced in number. Biopsies from adults presenting with liver disease typically show a nondescript cirrhosis with mild to moderate necroinflammatory activity.

A, Rounded eosinophilic cytoplasmic inclusions in periportal hepatocytes represent accumulation of α ₁ AT in endoplasmic reticulum in α ₁ AT deficiency. B, The inclusions are PAS-positive, diastase resistant. C, In infants with α ₁ AT deficiency who present with neonatal cholestasis, the cytoplasmic inclusions are inconspicuous; portal fibrosis and bile ductular reaction with associated prominent cholestasis may lead to an erroneous diagnosis of biliary disease.

α ₁ -ANTITRYPSIN DEFICIENCY—PATHOLOGIC FEATURES

Gross findings

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  Hepatomegaly with bile staining in young children

  
  
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  Cirrhosis in late stages

Microscopic findings

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  PAS-positive, diastase-resistant eosinophilic cytoplasmic globules in hepatocytes

  
  
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  Globules are more prominent in periportal hepatocytes and represent accumulation of α ₁ AT in endoplasmic reticulum

  
  
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  In neonates, bile ducts may be decreased in number

  
  
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  Chronic hepatitis pattern of injury with cirrhosis in adults

Ultrastructural findings

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  Amorphous proteinaceous material in endoplasmic reticulum

Genetics

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  Autosomal recessive disorder

  
  
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  Gene is located on chromosome 14q

  
  
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  α ₁ AT is a single-chain protease inhibitor in the Serpin family

  
  
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  Most common normal protein is M form; Z form is due to single base substitution

Immunohistochemistry

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  α ₁ AT accumulation is more pronounced in periportal hepatocytes

  
  
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  Granular accumulation in neonates, without globule formation

Differential diagnosis

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  Neonatal hepatitis

  
  
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  Biliary atresia

  
  
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  Paucity of intrahepatic bile ducts

  
  
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  Chronic viral hepatitis

  
  
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  Cryptogenic cirrhosis

Ancillary studies

Special stains

α ₁ AT cytoplasmic inclusions are strongly positive on PAS stain and resistant to diastase digestion. Immunohistochemistry is more specific and is particularly helpful in highlighting accumulation of the protein in liver biopsy samples from children, in which the globules may be small and inconspicuous. A finely granular cytoplasmic staining pattern with accentuation in periportal hepatocytes is typical in biopsy specimens from young children ( Fig. 18-6 ).

In biopsy samples from children, immunohistochemistry for α ₁ AT may be helpful and shows granular cytoplasmic accumulation, more prominent in periportal hepatocytes.

Differential diagnosis

In children presenting with neonatal cholestasis, the histologic differential diagnosis is broad and includes other causes of a neonatal hepatitis pattern of injury, as well as paucity of intrahepatic bile ducts. Immunohistochemical stains for α ₁ AT show granular accumulation of the protein in periportal hepatocytes and help suggest the diagnosis, which should be confirmed by protein electrophoretic testing. In adults with cirrhosis, the differential diagnosis includes chronic viral hepatitis and nonalcoholic steatohepatitis (NASH). Identification of characteristic cytoplasmic inclusions is highly suggestive but not pathognomonic of α ₁ AT deficiency; accumulation of the protein is also seen in end-stage liver disease associated with other causes and in livers with metastases.

Prognosis and therapy

Most children with α ₁ AT deficiency who present with liver disease show recovery of liver function. Elevated serum transaminase levels are adverse prognostic factors. Men older than 50 years (usually without a history of neonatal hepatitis) with α ₁ AT deficiency are at higher risk for cirrhosis. Liver disease in adults presenting with cirrhosis appears to show rapid progression, with death occurring within 2 years of the diagnosis of cirrhosis. A small increased risk for hepatocellular carcinoma in male patients with or without cirrhosis has been reported.

Therapy for liver disease associated with α ₁ AT deficiency is supportive, and there is no rationale for replacement therapy with α ₁ AT, because the liver injury is likely due to accumulation of the protein within hepatocytes. Augmentation of serum levels by the infusion of purified human α ₁ AT is approved for treatment of pulmonary disease.

Clinical features

The glycogen storage diseases (GSDs) are inherited disorders of glycogen metabolism; specific enzymatic defects in glycogen metabolism pathways result in accumulation of excess or structurally abnormal glycogen in the liver and other organs such as the heart, kidney, and skeletal muscle, depending on the metabolic defect. Because the liver and skeletal muscle normally has abundant glycogen, they are the most commonly affected tissues. GSD types I, II, III, IV, VI, and IX produce morphologic changes in liver; the most common form is GSD I. Most GSDs involving the liver present with hepatomegaly and hypoglycemia. All are autosomal recessive with the exception of some subtypes of GSD IX, which are X-linked.

Pathologic features

Microscopic findings

Hepatocytes in glycogen storage disease are swollen with excess free cytoplasmic accumulation of glycogen, which imparts a pale appearance ( Fig. 18-7 A and B). The sinusoidal compression and prominent hepatocyte cell membranes result in a mosaic appearance. Excess nuclear glycogen is seen in some but not all GSDs ( Table 18-1 ). The excess glycogen may be demonstrated by PAS stain, with removal of glycogen by diastase (see Fig. 18-7 C). The exception is GSD II, a lysosomal storage disorder; a mosaic pattern is not seen (see Fig. 18-7 D), hepatocytes demonstrate cytoplasmic lipid accumulation, and glycogen is found in lysosomes as beta particles. Hepatocellular adenomas develop in the setting of GSD I.

A, On low power, most of the glycogen storage diseases show a mosaic pattern. B, Cytoplasmic accumulation of glycogen in hepatocytes leads to a clear appearance on hematoxylin and eosin stain. C, PAS stain highlights the glycogen accumulation (shown), with removal of glycogen with diastase digestion. D, Type II GSD, a lysosomal storage disorder, does not show a mosaic pattern; hepatocytes contain lipid vacuoles.

TABLE 18-1

Glycogen Storage Diseases with Hepatic Manifestations

Glycogen Storage Disease	Clinical Presentation	Enzyme Deficiency	Histopathologic Findings
Type Ia (von Gierke’s disease)	Growth retardation, hepatomegaly, lactic academia, hyperlipidemia	Glycose-6-phosphatase in liver, kidney, intestine	Uniform mosaic pattern; excess glycogen and fat in hepatocytes; nuclear hyperglycogenation; hepatic adenomas
Type Ib	As for Ia; neutropenia and impaired PMN function	Transmembrane protein (translocase A1)	As for Ib, except mosaic pattern is nonuniform
Type II (Pompe’s disease)	Variable; cardiomegaly, hypotonia, hepatomegaly; adult presentation with only skeletal muscle involvement	Lysosomal acid α-glucosidase (acid maltase)	Nonmosaic pattern; intralysosomal glycogen accumulation; vesicular hepatocytes
Type III (Cori’s disease)	Similar to type I but less severe	Amylo-1, 6-glucosidase debranching enzyme	Uniform mosaic pattern; nuclear hyperglycogenation; may have portal septal fibrosis with progression to cirrhosis
Type IV (Andersen’s disease)	Hepatosplenomegaly and failure to thrive; hypoglycemia is rare	Branching enzyme	Cirrhosis before age 5; nonprogressive disease also exists; basophilic diastase-resistant cytoplasmic inclusions in hepatocytes
Type VI (Hers’ disease)	Hepatomegaly, growth retardation; variable hypoglycemia and hyperlipidemia, usually mild	Liver phosphorylase system; heterogeneous group of disorders	Nonuniform mosaic pattern; may have portal septal fibrosis
Type IX	As for type VI	Defect in one of four subunits of phosphorylase kinase	Nonuniform mosaic pattern; may have portal septal fibrosis or cirrhosis; low-grade necroinflammatory activity

 

PMN , polymorphonuclear.

GLYCOGEN STORAGE DISEASE—PATHOLOGIC FEATURES

Gross findings

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  Hepatomegaly

  
  
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  Liver is paler than normal

  
  
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  Fine fibrosis in types III and IV, with development of cirrhosis

Microscopic findings

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  Hepatocytes are enlarged by glycogen accumulation, with pale watery cytoplasm

  
  
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  Mosaic pattern due to compression of sinusoids and accentuation of hepatocyte cell membranes (type II lacks mosaic pattern)

  
  
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  In type IV, hepatocytes contain rounded basophilic cytoplasmic inclusions

  
  
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  Fibrosis leading to cirrhosis may be found in types III, IV, and VI

Ultrastructural findings

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  Large pools of glycogen displace cytoplasmic organelles

  
  
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  In type I, double-contoured vesicles are seen in the endoplasmic reticulum

  
  
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  In type II, glycogen accumulates in lysosomes

  
  
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  In type IV, non–membrane-bound inclusions are seen

Genetics

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  Autosomal recessive inheritance, except for some subtypes of type IX, which are X-linked

  
  
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  Type Ia: chromosome 17; G6P gene

  
  
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  Type Ib: chromosome 11q23; transmembrane transport protein (G6P receptor)

  
  
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  Type II: chromosome 17q25; acid maltase gene

  
  
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  Type III: chromosome 1p21; 1,2 amylo-1,6-glucosidase gene

  
  
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  Type IV: chromosome 3; branching enzyme gene

  
  
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  Type VI: chromosome 14; gene for subunit of liver phosphorylase isoform

  
  
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  Type IX: gene for subunit of phosphorylase kinase; genetically complex

Differential diagnosis

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  Normal liver

  
  
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  Type IV: Lafora’s disease

Ancillary studies

Differential diagnosis

For GSDs without hepatic fibrosis, the main differential diagnosis is normal liver, in which glycogen accumulation can be substantial. Diabetes mellitus is also associated with accumulation of hepatic glycogen. The GSDs may show considerable morphologic overlap with each other, and definitive diagnosis relies on biochemical testing of fresh or frozen liver tissue or other target tissue.

Prognosis and therapy

Prognosis depends on the biochemical defect. Many of the GSDs show clinical heterogeneity in presentation and outcome; severely affected patients often die in childhood, for instance, in GSD II, whereas other patients present as older adults with only skeletal muscle involvement.

For most GSDs, no specific treatment is available. Dietary manipulation in milder cases may be helpful; nocturnal nasogastric glucose drip feedings or ingestion of uncooked cornstarch prevents hypoglycemia and promotes normal growth in GSD I. Liver transplantation may be considered in cases with cirrhosis.

Clinical features

The lysosomal storage disorders (LSDs) most commonly involve glycolipid, phospholipid, or mucopolysaccharide metabolism and are characterized by accumulation of storage products in membrane-bound vesicles. The liver is affected in a number of these disorders, and storage product usually accumulates in both Kupffer cells and hepatocytes. Most LSDs are rare and exhibit an autosomal recessive inheritance pattern ( Table 18-2 ). Clinical progression varies widely, depending on the disorder.

TABLE 18-2

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