Liver biopsies can sometimes be almost normal on histological examination, even when performed for clinical indication. The clinical indication is typically abnormal liver enzyme elevations, but can be other laboratory abnormalities, such as elevated ammonia levels. Unexplained clinical findings or abnormal hepatic imaging can also prompt biopsy, such as ascites, hepatomegaly, or fevers of unknown origin. Generating a diagnosis and a differential can be very challenging when these biopsies appear almost normal on hematoxylin and eosin stain (H&E), or have minimal nonspecific changes. When minimal inflammation is the only finding, the differential is so long that it is essentially meaningless. However, these cases sometimes have subtle changes that can lead to a more specific diagnosis.
A specific diagnosis is most likely to be identified when using a disciplined, systematic approach. One approach is shown in Table 7.1, where the biopsy is systematically analyzed for subtle changes. Because the changes can be subtle, many cases benefit from being set aside and reexamined for clues a second time later that day or the next day. Additional H&E recuts can also help.
A broad differential for the almost normal liver biopsy is shown in Table 7.2. These entities are discussed in more detail in the relevant sections of this book, but this table provides a useful compilation of possible diagnoses when the biopsy looks almost normal. These entities are also briefly discussed in the next section. Following that, the differential for cryptogenic cirrhosis is briefly considered. Finally, the differential is discussed for the almost normal, nonfibrotic liver when all of the other potential causes discussed in this chapter have been carefully excluded.
In cases where no specific diagnosis is evident, the histological findings can still be valuable when they help clinicians to rule out specific clinical concerns; for example, autoimmune hepatitis in the setting of positive autoimmune markers or ruling out cirrhosis as the cause of portal hypertension.
7.2 CLINICAL HISTORY
Achieving a meaningful diagnosis in an almost normal liver biopsy depends heavily on integrating the clinical findings, laboratory findings, and histology findings. Important clinical information includes the use of medications, vitamins, and other herbal supplements. Histories of systemic illnesses are also very important, as many can involve the liver (discussed in more detail in Chapter 19). Family histories of unexplained liver disease in siblings or parents can be important clues. Some of the key aspects of integrating the liver enzyme patterns into the histology evaluation are discussed below. In addition, imaging studies of the liver are often performed prior to the biopsy and can help solidify the diagnosis in some cases. Vascular flow changes can be particularly subtle to diagnosis on histology, and the imaging can provide helpful corroboration.
Table 7.1 Approach to the almost normal liver biopsy
Questions
Comments
What clinical finding prompted the biopsy?
The clinical findings can provide critical clues that can help guide histology evaluation. This information is often not provided to the pathologists; it can be well worth the extra effort and phone calls to get it
What are the imaging findings?
Hepatomegaly? Vascular flow changes? Steatosis? Different imaging findings can help when evaluating liver biopsies
What are the lab tests?
What do the predominant enzyme patterns suggest?
Are the bile ducts normal?
Rule out ductopenia, subtle duct proliferation
Are the portal veins normal?
Rule out portal vein atrophy, loss, muscularization
Are the hepatic arteries normal?
Rule out amyloid
Are the hepatocytes normal?
Rule out inclusions, apoptosis, endoplasmic reticulum proliferation
Table 7.2 The differential for an almost normal liver biopsy includes these conditions
Diagnoses
Major findings
α-1-antitrypsin deficiency
Zone 1 hepatocytes with cytoplasmic globules—in infants and children, the globules may not be evident
Amyloid
Acellular deposits in sinusoids or vessels
Celiac disease
Mild nonspecific inflammatory changes
Crohn’s disease of the small bowel
Mild nonspecific inflammatory changes
Cystic fibrosis
Patchy areas of bile ductular proliferation and fibrosis. May also see nodular regenerative hyperplasia
Drug effect
Some can show minimal nonspecific inflammatory and reactive changes
Ferroportin disease
Moderate iron deposits, Kupffer cells >> hepatocytes, in a person with elevated ferritin but low transferrin saturation levels
Glycogenic hepatopathy
Big pale hepatocytes cells in a person with poorly controlled diabetes
Glycogen psuedoground glass inclusions
Large amphophilic hepatocyte inclusions in immunosuppressed patients on many medications
Hemochromatosis
Hepatocellular iron accumulation
Hepatoportal sclerosis
Loss or atrophy of portal veins, often accompanied by nodular regenerative hyperplasia
Hypervitaminosis A
Stellate cell hyperplasia
Ischemia, low grade
Scattered apoptotic cells in the lobules
Light chain deposition disease
Sinusoids lined by irregularly thickened deposits that can mimic pericellular fibrosis
Mitochondrial injury
Microvesicular steatosis
Nodular regenerative hyperplasia
Distinct nodularity to the liver parenchyma but without fibrosis; best seen on low-power magnification
Sickle cell hepatopathy
Dilated sinusoids, sickled red blood cells, Kupffer cell iron
Small bowel bacterial overgrowth
Mild nonspecific inflammatory changes
Thyroid disease
Mild cholestasis with hyperthyroidism
Fatty change (may be minimal) with hypothyroidism
Urea cycle defects
Affects all ages; can range from essentially normal to mild changes including fat and glycogenosis
Wilson’s disease
Mild fatty change with glycogenated nuclei
In some difficult cases, the diagnosis is only evident after an iterative process. First, the histology findings are discussed with the hepatologist/clinician and with the radiologist. Next, each of these three groups of experts then take the information obtained from the discussions and go back and reexamine the patient, the histology, and the radiology. A subsequent joint discussion can then often bring the proper diagnosis into focus or suggest further lines of investigation. This process is the most effective method for making the best diagnosis in the most difficult cases. Unfortunately, time pressures and other complexities in the practice of modern medicine make this very challenging to do on a routine basis. That being said, there is no substitute as effective as this iterative process in resolving the most challenging cases.
7.3 CLUES IN THE LIVER ENZYMES
Alkaline phosphatase
A predominately alkaline phosphatase elevation (compared to aspartate transaminase (AST) and alanine transaminase (ALT)) is most commonly seen in the setting of biliary tract disease. In this situation, AST and ALT levels are also commonly above normal, but typically less than 5× the upper limit of normal. Examine the biopsy carefully for evidence of bile duct injury, including bile ductular proliferation and ductopenia. The differential for a predominant elevation in the alkaline phosphatase levels also includes granulomatous disease, nodular regenerative hyperplasia, chronic venous outflow impairment, and sinusoidal infiltrative processes. A subset of patients with nonalcoholic fatty liver disease can also present with isolated alkaline phosphatase elevations, particularly older aged women.1 The histology findings in these cases can range from minimal steatosis to active steatohepatitis with cirrhosis.
Don’t forget that there are nonhepatic causes for alkaline phosphatase elevations (Table 7.3); these possibilities should be considered more strongly if the liver is negative after full histological evaluation. Serum γ-glutamyltransferase levels can also be helpful, as they are elevated with liver disease but not in the conditions listed in Table 7.3.
Low levels of alkaline phosphatase are only rarely encountered, but the differential includes Wilson disease, generalized malnutrition, and hypothyroidism.2
Table 7.3 Nonhepatic causes of persistent elevations in serum alkaline phosphatase levels
Causes
Bone disease
Renal failure
Heart failure
Malignancy (e.g., lymphoma)
Parathyroid disease
Thyroid disease
Pregnancy
AST and ALT
Predominate elevations in the AST and ALT (compared to alkaline phosphatase) usually indicate a hepatitis injury pattern or a direct toxin exposure. In many cases of inflammatory hepatitis, such as viral hepatitis, the AST is less elevated than the ALT. In contrast, as we all learned in medical school, the AST is often 2× or greater than the ALT in alcohol-related liver disease. However, this observation is most useful as an exam question for medical students, as the clinical reality is much more complicated, with many exceptions,3 including alcoholic hepatitis that does not show this AST:ALT relationship, as well as non-alcohol-related diseases that do.
Isolated hyperammonemia
Isolated elevations in serum ammonia are seen primarily with urea cycle defects4 or with drug effects, in particular valproate.5 The biopsies can look normal or have mild and nonspecific changes (Fig. 7.1). In the transplant setting, isolated hyperammonemia can result from anastomotic strictures of the portal or hepatic veins or with a patent portosystemic shunt.6 Many of the transplant patients in this setting also have ascites from the anastomotic strictures.
7.4 PORTAL TRACT CHANGES
Bile duct changes
The biopsy should be examined for bile duct changes, including ductopenia, cholangitis, periductal fibrosis, duct duplication, or ductular proliferation. In all of these settings, the alkaline phosphatase should be elevated. The most commonly used definition for ductopenia is loss of 50% or more of the bile ducts. Immunostains such as CK7 or CK19 can highlight both bile duct loss and/or subtle bile ductular proliferation. Copper stains may also be useful if a biliary disease is in consideration.
Figure 7.1 Almost normal biopsy, isolated hyperammoniemia. This biopsy is from a patient taking valproic acid. There was very focal fatty change and rare foci of lobular inflammation, but the biopsy was otherwise normal.
Portal vein changes
Portal vein changes can be subtle, but can include portal vein muscularization (Fig. 7.2), thrombosis (Fig. 7.2), portal vein herniation (Fig. 7.3), and portal vein atrophy or loss. There is no well-established cutoff for determining portal vein loss, but the changes should be convincing and reasonably diffuse to be diagnostically useful. Portal vein atrophy is even more challenging to confidently diagnose in the early stages. When most of the portal veins are clearly smaller than normal, this diagnosis should be considered. In many cases with portal vein abnormalities, the lobules will show nodular regenerative hyperplasia-like changes.
Figure 7.2 Portal vein thrombosis. The portal vein is thrombosed. In response, the portal vein wall had developed striking muscularization.
Figure 7.3 Portal vein herniation. In this case of portal vein thrombosis, the portal vein appears to herniate out of the portal tract into the adjacent parenchyma.
Hepatic artery changes
Hepatic artery changes in the nontransplant setting can be very subtle. Look carefully for amyloid, as some types of familial amyloid can have a predominately arterial pattern of amyloid deposition (Fig. 7.4). Hepatic artery arteriolosclerosis can be seen in the setting of hypertension and/or diabetes,7 particularly in the elderly, but usually this is an incidental finding (Fig. 7.5).
Figure 7.4 Familial amyloidosis, Congo red stain. The biopsy was essentially normal on H&E, but a Congo red stain showed amyloid deposition limited to the hepatic arteries.
Figure 7.5 Hepatic artery, hypertensive changes. The walls are thickened and hyalinized.
7.5 HEPATOCYTE CHANGES
The hepatocytes should be examined carefully in the almost normal liver biopsy for any changes, even if the changes are mild and patchy. Hepatocyte changes generally fall into the category of either subtly increased apoptosis or abnormal cytoplasmic changes. A subtle increase in apoptosis, without significant inflammation or cholestasis, usually results from a mild drug effect, early acute viral hepatitis, or low-grade or transient ischemia.
Increased hepatocyte apoptosis is almost invariably accompanied by increased hepatocyte proliferation, which can be highlighted by a Ki-67 immunostain. In this regard, a Ki-67 stain can show active regeneration even if apoptotic bodies are sparse or subtle, serving as an excellent screen for a recent or ongoing liver injury that has led to active hepatocyte regeneration. The opposite is also true: a Ki-67 immunostain can help identify impaired liver regeneration, when there is active hepatocyte injury, but little or no regeneration.
Abnormal cytoplasmic changes include the presence of globules, such as those seen with α-1-antitrypsin deficiency, megamitochondria, ground glass changes, pseudground glass changes, glycogenosis, microvesicular steatosis, cholestasis, or other pigment accumulation.
Eosinophilic globules
The globules of α-1-antitrypsin deficiency are typically in zone 1 hepatocytes. Not all hepatocytes will have globules, but those that do will have multiple globules. The globules can be highlighted by a PASD stain or by an immunostain.
Prominent megamitochondria are most commonly seen in the setting of fatty liver disease or with cholestatic liver disease, in which case they are considered to be part of the ordinary disease pattern and are ignored. However, in rare biopsies the only significant finding is that of prominent hepatocyte megamitochondria. In adults, this findings can be associated with drug effects, though usually the biopsy will also have other findings to point to a possible drug reaction, such as mild inflammatory changes.8 In children, prominent megamitochondria can be seen as one of the earliest changes in several different metabolic diseases, including inherited mitochondrial defects, various urea cycle defects, or with other inherited metabolic defects, such as lysinergic protein intolerance (Fig. 7.6) or hypermethioninemia.9
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