—  SPECIALTY CONFERENCE  —

Liver Pathology

Case 1 - Glycogenic Hepatopathy

Linda D. Ferrell
University of California
San Francisco, CA





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Clinical History:
12 ear old male with diabetes, Type 1, poorly controlled
The patient presented to emergency room with ketoacidosis
PE: Hepatomegaly, RUQ pain
Lab: Increased ALT/AST 2x normal, Glucose 635; HbA1c 13.5 (nl<6)
Patient admitted
Ultrasound suggested fatty liver
Liver biopsy performed
Biopsy slide referred to UCSF to exclude glycogen storage disorder
Patient treated for ketoacidosis, hyperglycemia
Transaminases returned to normal, and liver decreased in size
No known long-term sequelae


Case 1 - Figure 1 - Low magnification of needle biopsy shows diffuse pale staining of hepatocytes in a panacinar pattern (H&E, 10x)
Case 1 - Figure 2 - Pale and swollen hepatocytes in periportal area. No periportal fibrosis is present. Some nuclei contain glycogen vacuoles. The hepatocellular changes are due to increased glycogen in hepatocytes. (H&E, 20x)
Case 1 - Figure 3 - Pale swollen hepatocytes in periportal area (zone 1). No periportal fibrosis is present. Some nuclei contain glycogen vacuoles. Only very scant inflammation is present in portal zone. (H&E, 40x)

Case 1 - Figure 4 - Markedly swollen and pale hepatocytes around central zone (zone 3). A few hepatocytes may contain small fat droplets (H&E 40x)
Case 1 - Figure 5 - Markedly swollen and pale hepatocytes in midzone (zone 2), and minimal lobular inflammation in sinusoids. (H&E, 40x)


Differential Diagnosis:
Glycogenic hepatopathy
Glycogen storage disorder
Nonalcoholic fatty liver disease
Nonalcoholic steatohepatitis, including pediatric and subacute variants
Other possibilities, but unlikely: Glycogen pseudoinclusions and Wilson Disease

Final Diagnosis:
Glycogenic Hepatopathy

The following was adapted from:
Glycogenic Hepatopathy: An Under-Recognized Hepatic Complication of Diabetes Mellitus. Amer J Surg Pathol 2006;30:508-513

Coauthors of original manuscript:
Michael Torbenson, M.D., The Johns Hopkins University School of Medicine, Baltimore
Yunn-Yi Chen, M.D., Ph.D., University of California San Francisco, San Francisco, CA
Elizabeth Brunt, M.D., Saint Louis University Liver Center, Saint Louis University School of Medicine, St. Louis, MO
Oscar W Cummings, M.D., University Hospital, Indianapolis, IN
Marcia Gottfried, M.D., Duke University Medical Center, Durham, NC
Shriram Jakate, M.D., FRCPath, Rush University Medical Center, Chicago, IL
Yao-Chang Liu, M.D., Case Western Reserve University, MetroHealth Medical Center, Cleveland, OH
Matthew M. Yeh, MD, Ph.D., University of Washington Medical Center, Seattle, WA
Linda Ferrell, M,D., University of California San Francisco, San Francisco, CA

Introduction
Liver pathology in individuals with type II diabetes mellitus has been well characterized and ranges from minimal non-specific inflammatory changes to non-alcoholic fatty liver disease (NAFLD). [16] NAFLD is a term that includes both simple fatty change as well as non-alcoholic steatohepatitis (NASH). [4] The histological findings in NAFLD reflect dysregulation of fat and glucose metabolism coupled with other incompletely understood factors leading to hepatic inflammation. [6] While liver biopsy specimens in type I diabetics, like type II diabetics, can show NAFLD, [12] biopsy specimens in type I diabetics can also show a unique pathological change that we have designated glycogenic hepatopathy (GH).

GH can present with different clinical signs and symptoms, the most dramatic being a syndrome first described by Mauriac of growth retardation, hepatomegaly, cushingoid features, and delayed puberty. [13] While the Mauriac syndrome was first described 75 years ago, the histological findings of GH remain under-recognized. The group of authors in this study have encountered cases of GH that posed diagnostic challenges to clinicians and pathologist based on the relative lack of awareness of this entity. For example, three of the cases in this study were sent in consultation (to LF, MY) with an original diagnosis of glycogen storage disease.

Clinical and Laboratory Findings
The clinical manifestations of glycogenic hepatopathy include hepatomegaly, abdominal pain, and other symptoms such as nausea and vomiting. Elevated serum glucose levels are typical. Other clinical findings include ketoacidosis and elevated hemoglobin A1c levels, indicating poor long-term glycemic control. Rarely, hypoglycemia and ascites are present. The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels vary significantly, from normal (1/14 cases, 7%) to marked elevations that are in some cases 10 times or greater than the upper limits of normal (3/14 cases, 21%). Modest serum alkaline phosphatase elevations are also common.

Histological Findings
Overall, the liver parenchyma and architecture are preserved. The most striking finding is a diffuse hepatocellular change characterized by pale hepatocytes with cytoplasmic rarefaction and accentuation of the cell membranes. Sinusoids often appeared compressed by the swollen hepatocytes. Glycogenated nuclei may be numerous. Abundant cytoplasmic glycogen deposits can be demonstrated by PAS stains which disappear after digestion with diastase. The presence of glycogen accumulation in the cytoplasm and in some nuclei can be confirmed on ultrastructural examination. [12]

Steatosis can be absent or mild. Only one of our cases showed changes sufficient for a diagnosis of mild steatohepatitis. Overall, inflammation is absent or minimal. Two of our cases showed mild fibrosis, one with periportal fibrosis and the other with pericellular fibrosis; the latter being the case with concurrent mild steatohepatitis. Acidophil bodies are rare. Giant mitochondria were commonly found.

Clinical Course
Three patients in our study had adequate follow-up and all showed improvement of transaminase levels and reduced hepatomegaly with control of blood glucose. One of these patients had a follow-up liver biopsy that demonstrated an essentially normal liver.

Discussion
Glycogen loading of the liver was first documented as a component of Mauriac's syndrome in 1930 [13] . In this syndrome, glycogen loading, hepatomegaly, and abnormal liver enzymes are associated with other features including growth retardation and/or dwarfism, delayed puberty, cushingoid features and hypercholesterolemia. Over time, it has been recognized that glycogen loading can be present without the full spectrum of changes seen in the Mauriac syndrome. [12] This process has variably been referred to as hepatic glycogenosis, [3] liver glycogenosis, [2] liver glycogen storage, [7, 21] and diabetes mellitus-associated glycogen storage hepatomegaly. [17] We recognize that any of these terms may be reasonable nomenclature for this lesion. However, we propose the term "glycogenic hepatopathy" for this pattern of glycogen-loading of the hepatocytes in the clinical setting of either hepatomegaly or elevated transaminase levels, as we suggest the term "glycogen hepatopathy" better reflects the non-inflammatory pathological findings.

Our cases show similar clinical and histological features to those described by others. [2, 3, 7, 15, 17, 18, 21] Based on our results and those of others (Table 1), individuals with GH can be adults or children with marked or prolonged hyperglycemia who are treated with insulin, usually in the setting of Type I diabetes mellitus. Most individuals had poor glycemic control and elevated liver transaminases. All individuals with available clinical history had hepatomegaly. Coincidental fatty change or NASH was uncommon (<20% in combined studies) and no evidence was noted for the development of significant fibrosis or cirrhosis as can be seen in NASH.

Glycogenic hepatopathy appears to be under-recognized by clinicians, radiologists, and pathologists, even though this entity has been described several times over the years in the medical literature. This may be due to both the rarity of this lesion as well as to the more common (and current) emphasis on fatty liver disease. [5] Glycogenic hepatopathy has not been reported in the pathology literature, which may further limit the exposure of pathologists to this entity. In addition, ultrasound does not distinguish fatty liver from glycogen overload [2, 3, 15, 21] , so clinicians may assume that a patient with hepatomegaly has fatty liver if no biopsy is obtained.

The histology of GH demonstrates these key features (1) marked glycogen accumulation leading to pale, swollen hepatocytes, (2) no or mild fatty change, (3) no or minimal inflammation, (4) no or minimal spotty lobular necrosis, and (5) intact architecture with no significant fibrosis. The key clinical features are hepatomegaly and elevated transaminases, which in some cases can be dramatically elevated. Even in those cases with marked transaminase elevations, there is no histological evidence that the enzyme elevations are due to liver necrosis per se, and their elevation presumably reflects sufficient hepatocyte injury to cause enzyme "leakage" instead of cell death. We suspect a similar mechanism (marked accumulation of hepatocellular glycogen leading to enzyme leakage) explains the observations of transient elevations in liver transaminases following insulin loading to treat diabetic ketoacidosis. [1, 19] In GH, liver transaminases typically return to normal with adequate control of blood sugar levels, even in those cases with marked enzyme elevations. [2, 3, 15, 18, 20] As seen in one of the cases in our study, ascites can also rarely be part of the clinical presentation of GH. The underlying pathophysiology is unclear, but may involve sinusoidal compression by the glycogen-laden hepatocytes. Ascites has been reported in the setting of GH previously, [1, 3] and improved significantly with adequate control of blood sugar.

GH is also known to occur in one additional clinical setting: following short term high-dose steroid therapy. [10] The clinical presentation of hepatomegaly and elevated transaminases elevations as well as the histological findings are identical to that seen in the setting of diabetes mellitus and imply a common mechanism of glycogen trapping within hepatocytes. The ability of steroids to induce GH has been confirmed by animal studies. [8]

Mechanistically, GH results from excess accumulation of glycogen in hepatocytes, occurring when marked or prolonged hyperglycemia is treated with insulin. [15] Glucose in the sinusoidal blood is rapidly taken-up by hepatocytes and this is followed by rapid conversion of the glucose to glycogen, which is then trapped within the liver (Figure 1).

GH is not the only pathological finding seen in type I diabetes mellitus. In a study of liver biopsy findings in 99 cases of hepatomegaly in diabetic children, Lorenz and B ä renwald found most cases of hepatomegaly were related to glycogen accumulation, with moderate glycogen accumulation in 22% of cases and pronounced glycogen accumulation in 19% of cases. [12] Fatty liver appeared to explain the hepatomegaly in another 8% of individuals, though mild fatty change was seen in nearly half of the total number of cases overall. The differential for elevated liver enzymes in type I diabetes also includes drug effect as well as hepatosclerosis, in which dense fibrosis is deposited in the perisinusoidal spaces in a non-zonal fashion in the absence of NAFLD or GH. [9]

At the time of GH presentation, the clinical differential usually includes NAFLD, from which GH is histologically easily distinguished as discussed above. After histological review, the differential diagnosis may also include the possibility of glycogen storage disease. [11, 14] The hepatocytes in both entities are markedly swollen and filled with glycogen. While a subtle clue can be the presence of greater cytoplasmic clumping of glycogen in glycogen storage disease, there can be significant histological overlap. However, clinical parameters, such as the poorly controlled diabetes and response to diabetic control of GH, are key features to distinguish this entity from a glycogen storage disorder.

In conclusion, GH most commonly occurs in individuals with type I diabetes mellitus and poorly controlled blood sugar. Clinically, the presentation varies but typically includes hepatomegaly and transaminase elevations. Histologically, GH manifests as large, swollen, glycogen-laden hepatocytes without significant fatty change, inflammation, lobular spotty necrosis, or fibrosis. The pathology is distinct from steatohepatitis.

References
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  3. Chatila R, West AB. Hepatomegaly and abnormal liver tests due to glycogenosis in adults with diabetes. Medicine (Baltimore) 1996; 75:327-333.

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  13. Mauriac P. Gros ventre, hepatomegalie, troubles de las croissance chez les enfants diabetiques traits depuis plusieurs annes par l'insuline. Gax Hebd Med Bordeaux 1930; 26:402-410.

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  17. Nakamuta M, Ohashi M, Goto K, Tanabe Y, Hiroshige K, Nawata H. Diabetes mellitus-associated glycogen storage hepatomegaly: report of a case and review of the Japanese literature. Fukuoka Igaku Zasshi 1993; 84:354-358.

  18. Olsson R, Wesslau C, William-Olsson T, Zettergren L. Elevated aminotransferases and alkaline phosphatases in unstable diabetes mellitus without ketoacidosis or hypoglycemia. J Clin Gastroenterol 1989; 11:541-545.

  19. Takaike H, Uchigata Y, Iwasaki N, Iwamoto Y. Transient elevation of liver transaminase after starting insulin therapy for diabetic ketosis or ketoacidosis in newly diagnosed type 1 diabetes mellitus. Diabetes Res Clin Pract 2004; 64:27-32.

  20. Tomihira M, Kawasaki E, Nakajima H, Imamura Y, Sato Y, Sata M, Kage M, Sugie H, Nunoi K. Intermittent and recurrent hepatomegaly due to glycogen storage in a patient with type 1 diabetes: genetic analysis of the liver glycogen phosphorylase gene (PYGL). Diabetes Res Clin Pract 2004; 65:175-182.

  21. Torres M, Lopez D. Liver glycogen storage associated with uncontrolled type 1 diabetes mellitus. J Hepatol 2001; 35:538.


Additional references:


  1. Wisell J, Boitnott J, et al. Glycogen Pseudo-Ground Glass change in Hepatocytes. Amer J Surg Pathol 2006; 30:1085.

  2. Caldwell and Hespenheide. Subacute liver failure in obese women. Am J Gastroenterol 2002; 97:2058-62

  3. Schwimmer JB, Behling C, et al. Histopathology of pediatric nonalcoholic fatty liver disease. Hepatol 2005; 42:641.

  4. Nobili V, Marcellini M., et al. NAFLD in children: A prospective clinical-pathological study and effect of lifestyle advice. Hepatol 2006;44:458.

  5. Portmann B, et al. Genetic and metabolic liver disease, In: MacSween's Pathology of the Liver, 5th ed. (Eds: Burt, Portmann, Ferrell), Churchhill Livingstone, 2006, p. 199.