Pathophysiology of disease (V)

It’s been a while since I read stuff from this book, but I’m behind on the blogging so I decided to have a second look at some of that stuff. I never really got to talking much about chapter 14 (about liver disease) in my last post, and since then I’ve also read about disorders of the exocrine pancreas (chapter 15), renal disease (chapter 16), disorders of the parathyroids and calcium metabolism (chapter 17), and disorders of the endocrine pancreas (chapter 18). In this post I’ll limit my coverage to liver disease – it’s a fairly long chapter and these posts take quite a bit of time.

Before I start out with the main coverage, I should note that the one main take-away from this chapter is that the liver does a huge amount of different stuff. There’s a reason we can’t live without this organ (or perhaps a better way to think about this is that there are rather lots of reasons).

Anyway, on to the chapter coverage. The chapter starts out with a brief overview of how liver disease presents and some key concepts. Overview of the structure and function of the liver (anatomical- and histological features etc.) then follows, description of blood flow to the organ, and a description of the various functions the liver has (energy metabolism; protein synthesis; solubilization, transport and storage functions; protective and clearance functions). Then an overview of liver disease follows – what goes wrong, how it manifests, etc. Given how many functions the liver has, liver disease can cause a lot of problems with a lot of different things, and I decided to cover this part in a bit of detail below. First of all, problems with the liver can mess up all kinds of metabolic processes: Altered carbohydrate metabolism secondary to liver disease may cause hypo- or hyperglycemia, altered lipid metabolism may cause fat accumulation within the liver or elsewhere in the body, whereas altered protein metabolism may cause altered mental status and even coma (hepatic encephalopathy). Bile (a fluid produced by the liver to help with digestion) secretion failure, termed cholestasis, may cause various forms of malabsorption and deficiency states – classical signs of liver disease, jaundice and icterus (yellow discoloration of sclera (the whites of the eyes) and skin), are both caused by build-up of bilirubin caused by cholestasis. Most people are aware of the liver’s role in drug metabolism, and of course a failing liver will not clear drugs as well as a healthy liver will; a problematic aspect in particular here is that impaired clearance may make individuals abnormally sensitive to the toxic effects of drugs. Incidentally the liver clears drugs and other things through various phases, which means that different types of liver cells end up getting exposed to different types of compounds; the liver isn’t just a big clump of cells which tend to get harmed the same way by hepatotoxic substances. Rather what happens in cases of hepatotoxic exposures is that different liver cells are harmed by different compounds in foreseeable ways, so that direct poisons harm the first clearance zones hardest, whereas other hepatotoxic substances will harm cells ‘further down the line’ which are the ones that get exposed to the toxic metabolites generated earlier in the process – sometimes it’s not the stuff that goes in which is toxic, but rather the stuff the liver cells need to convert it into to get it out of the system. Anyway, aside from the stuff already mentioned the liver also has a role in storing various substances, which means that liver dysfunction may cause vitamin deficiency states. The liver produces proteins which have various functions throughout the body and when its function is impaired critical proteins may not be produced in the necessary quantities, causing problems such as hypoalbuminemia-related edema (fluid build-up in tissues). Clotting factors are also produced by the liver and lack of those may lead to various coagulopathic states (bleeding disorders). Altered hormone clearance in the liver may cause things like elevation of blood estrogens, which may cause physiological changes such as gynecomastia. Liver failure may cause the kidneys to retain salt and water as a defence mechanism, and so patients with severe liver disease may develop kidney failure as a result of these processes. Ascites, excess fluid build-up in the peritoneal cavity, may develop through a ‘complex and multifactorial’ process. A particularly awful type of bad breath called fetor hepaticus may develop in late-stage liver disease.

As you can probably tell from the comments above, all in all there are a lot of ways in which a bad liver can screw you over. It does a lot of good things, so a lot of things can go wrong.

After covering general aspects of liver disease, the pathophysiological aspects of a few specific liver diseases are covered in the last part of the chapter. This part deals with acute hepatitis, chronic hepatitis, and cirrhosis. Various specific disorders and disease processes may cause each of these (with huge variation in symptoms/presentation and severity of disease), so the extent to which specific disorders are dealt with in detail in this part of the chapter may be debatable – but it’s good stuff anyway. I decided not to cover the stuff in that part of the chapter in great detail but I do want to give a brief overview with some key points, and actually a pretty good big-picture short version of many of the relevant clinical distinctions is given in the beginning of the chapter:

“Although many different pathogenic agents and processes can affect the liver […], they are generally manifested in individual patients in a limited number of ways that can be assessed by evaluation of some key parameters. Liver disease can be acute or chronic; focal or diffuse; mild or severe; and reversible and irreversible. Most cases of acute liver disease (eg, due to viral hepatitis) are so mild that they never come to medical attention. […] The patient recovers without any lasting medical consequences. In other cases of acute liver injury, symptoms and signs are severe enough to call for medical attention. The entire range of liver functions may be affected or only a few […] Occasionally, viral and other causes of acute liver injury occur in an overwhelming manner with massive liver cell death. This syndrome of fulminant hepatic failure carries a high mortality rate, but if the patient survives, liver function returns to normal and there is no residual evidence of liver disease.
Liver injury may continue beyond the initial acute episode or may be recurrent (chronic hepatitis). In some cases of chronic hepatitis, liver function remains stable or the disease process ultimately resolves altogether. In other cases, there is progressive and irreversible deterioration of liver function.

Cirrhosis is ultimately the consequence of progressive liver injury. Cirrhosis can occur in a subset of cases of chronic hepatitis that do not resolve spontaneously or after repeated episodes of acute liver injury, as in the case of chronic alcoholism. In cirrhosis, the liver becomes hard, shrunken, and nodular and displays impaired function and diminished reserve due to a decreased amount of functioning liver tissue. More importantly, the physics of blood flow is altered such that blood in the hepatic portal vein is diverted around the liver rather than being filtered through the liver. This phenomenon, termed portal-to-systemic shunting, has profound effects on the function of various organ systems and sets the stage for certain devastating complications of liver disease […]

The consequences of liver disease can be either reversible or irreversible. Those arising directly from acute damage to the functional cells of the liver, most notably hepatocytes, without destruction of the liver’s capacity for regeneration, are generally reversible. Like many organs of the body, the liver normally has both a huge reserve capacity for the various biochemical reactions it carries out and the ability to regenerate fully differentiated cells and thereby recover completely from injury. Thus, only in the most fulminant cases or in end-stage disease are there insufficient residual hepatocytes to maintain minimal essential liver functions.”

Some related comments from the last half of the chapter:

Based on clinical, laboratory, and biopsy findings, chronic hepatitis is often divided into two classes: chronic persistent and chronic active hepatitis. Chronic persistent hepatitis is seldom progressive despite persistent biochemical abnormalities reflecting ongoing liver cell necrosis. The clinical course is relatively benign, often characterized by spontaneous resolution (eg, clearance of persistent viral infection). Chronic active (aggressive) hepatitis is typically progressive, often resulting ultimately in cirrhosis and its complications or liver failure and death.” […] The complications of chronic active hepatitis are those of progression to cirrhosis – variceal bleeding, encephalopathy, coagulopathy, hyperspleenism, and ascites. These are largely due to portal-to-systemic shunting rather than diminished hepatocyte reserve” […]

“Either type of chronic hepatitis can be caused by infection with several hepatitis viruses (eg, hepatitis B with or without hepatitis D superinfection and hepatitis C); a variety of drugs and poisons (eg, ethanol, isoniazid, acetaminophen), often in amounts insufficient to cause symptomatic acute hepatitis; genetic and metabolic disorders (eg, α₁-antiprotease (α₁-antitrypsin) deficiency, Wilson’s disease, and hemochromatosis); or immune-mediated injury of unknown origin. […] A specific cause can be determined for only 10-20% of patients. […]

“As with other presentations of liver disease, not all patients with cirrhosis develop life-threatening complications. Indeed, in nearly 40% of cases, cirrhosis is diagnosed at autopsy in patients who did not manifest obvious signs of end-stage liver disease.”