Approach to and Evaluation of Metabolic Liver Diseases

Introduction

The liver is, arguably, the principal orchestrator of metabolism in the body, essentially acting as the responder, arbiter, and transformer of the molecules of life. It is anatomically positioned to be the first organ to receive substances from the gut (food as well as various ingestions and molecules from microbes), spleen, endocrine pancreas, and visceral fat stores, thereby integrating multiple molecular inputs. Moreover, from a microvascular standpoint, the sinusoidal endothelium is fenestrated, thereby placing no impediment for portal blood contents to directly contact hepatocytes that have variable functions in the different zones of the liver lobule. The hepatocytes are, therefore, the shield, deflector, and biotransformer/repository for a variety of molecules to then be repackaged before either secretion into the circulation (e.g., lipoprotein particles, glucose) or to be destined for elimination into bile (e.g., toxins, conjugated bilirubin, bile acids). The molecules that hepatocytes are destined to handle are either exogenous in origin (e.g., food substances, toxins, drugs) or from an endogenous source (various lipids from visceral fat stores, carbohydrates). Of the approximately 23,000 genes in humans, approximately 11,000 are actively transcribed in hepatocytes, many of which are related to the unique integrated metabolic functioning of hepatocytes.

Thus it should come as no surprise that metabolic derangements and progression of liver damage can develop when one or more of these crucial genes are mutated and functionally inadequate. This occurs when the function of these genes cannot be supplanted by that of another gene, and therefore nonredundancy is an obligate setting for impairments in the metabolic pathway of interest and the physiologic consequences thereof. Broadly, such disorders are termed metabolic liver diseases , and these often present in infancy and early childhood because there are great metabolic demands at this time of life (mostly due to the need to grow) but also because ex utero , the infant's genes are being used without the support of the linked maternal circulation. But it should be noted that there is no time of life when genetic variants that underlie metabolic liver disease are not possible causes or modifiers of another reason for liver dysfunction.

General Approach and Clinical Evaluations

In essence, the broadest definition of metabolic liver disease is a condition or setting where a genetic variant negatively impacts liver development, basal functioning, or adaptations to a stressor. Given the essential role of the liver in the body's metabolism of nutrients (carbohydrates, proteins, fats) and their subsequent storage, packaging, and delivery to other tissues, it is not surprising that reduced functioning of key enzymes encoded by genes with less-functional variants will lead to disease due to either an absence of a needed end product (e.g., glucose from glycogen) or the accumulation of toxic intermediate molecules upstream of a block in a sequential metabolic pathway (e.g., atypical bile acid intermediates in bile acid synthesis defects). It is also clear that some metabolic diseases are evident from global alterations in subcellular organelle structure and function, which for the liver often involve mitochondria or peroxisomes.

There are select clinical situations where the patient is noted to be impaired from birth (respiratory difficulties, organomegaly) but often metabolic diseases can take months to years to present. It is likely that expression of many of the genes involved in core aspects of metabolism may be further reduced in the setting of a stressor, often an infection or exposure to a new medication. Thus a previously normal child may, at 5 years to 10 years of age, after a seemingly insignificant viral infection, become jaundiced, obtunded, and have markedly elevated serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels from hepatocellular destruction initially ascribed to a direct viral effect on hepatocytes (see later). Moreover, as a component of the negative hepatic acute phase response, many genes involved in key metabolic pathways are naturally reduced in expression because of inflammation. If one of these genes also has a significant sequence variant that impacts the encoded enzyme's functioning, then one can see the additive effects of inflammation-mediated reductions in gene expression combined with a basally reduced function due to the sequence variant, which together can lead to serious metabolic consequences uncovered during this time of illness. In general terms, many enzymes function at higher than their threshold capacity and thus can adequately perform day-to-day functions even with sequence variations. But when there is an additional hit, the system may not be adequately counterbalanced, harmful abnormal metabolites accrete, and liver disease may ensue. This is often a clinically useful paradigm to consider when one is presented with patients who may have metabolic liver diseases yet have had no significant indication of metabolic impairments beforehand.

Thus the lack of disease in infancy or early childhood should not provide the clinician with the solace that a patient's clinical disease is not metabolic in origin—rather this particular episode tipped the balance from acceptable functioning of the pathway to one that is unacceptable. Stressors other than infection can also lead to a clinical uncovering of metabolic liver disease, including puberty, aging, surgery, medications, starvation, and obesity. The prepared clinician can help uncover those situations where this may in fact be at play. This chapter is focused on helping clinicians to recognize when metabolic liver diseases may be primary components of a patient's presentation and overall well-being.

Diagnostics for Metabolic Liver Diseases

There are a number of clinical clues that suggest a patient may have a metabolic liver disease. Excluding the contributions of the two most prevalent genetic liver diseases in U.S. populations, α ₁ -antitrypsin deficiency and hereditary hemochromatosis (due to specific variants in the SERPINA1 and HFE genes), Table 62-1 lists common clinical conditions or indications that should prompt a clinician to consider exploring the potential for metabolic liver disease.

As can be gleaned from Table 62-1 , the presentations of many conditions substantially overlap, often without pathognomonic features that can lead to one, and only one, diagnosis. For example, many different liver diseases present in infancy with hypoglycemia as a key clinical feature, due to a global hepatocellular metabolic impairment in either the accumulation or the degradation of glycogen. This may lead some clinicians to focus exclusively on genetic disorders of glycogen metabolism and explore the group of glycogen storage diseases as primary diagnostic possibilities, yet hypoglycemia may just be a feature of intermediary metabolic derangements from a completely different disorder.