In the upper right quadrant of the abdominal cavity is a large red mass that may look like a sleeping giant. It doesn't pulsate, it doesn't move much, only passively, and you don't ordinarily see it secreting anything. This soft, almost jelly-like mass is the liver. Without it the body is kaput. Fortunately, a body can survive on about one-third the amount of liver that the normal person has. What this brooding shapeless hulk of red does is a subject of this minicourse. Where else can a body produce that nice green stuff called bile so easily, and what would a person do without all those plasma proteins to make the minicourse on capillaries come out right and what would the pharmacologist do without the liver to detoxify drugs?

The pancreas is something else. It couldn't decide whether to be fish or fowl, so it decided to be both. Exocrine and endocrine. Fortunately, it doesn't try to be both ways in the same way. It is little islets of endocrine in a sea of exocrine. That great explorer Langerhans planted his flag on one of these islets and claimed it for King Endocrine for all time. Being somewhat persnickety he decried that the products of his islets would only be shipped via the good ship Plasma, while the poor exocrine people had to build their own canals which they dressed up with the name ducts. (Liver and onions will be served in the mess hall tonight.)

1.3 Liver, Gallbladder, Pancreas, and Related Organs

On completion of this minicourse you will be able to:
  1. Describe the shape and position of the normal liver.
  2. Describe the following in terms of location, structure and function:
    1. liver lobule
    2. portal triad
    3. venous drainage of the liver
    4. hepatic artery
    5. hepatic portal vein
  3. Describe the major features of the hepatic portal system.
  4. Describe the following functions of the liver:
    1. production of bile
    2. production of plasma protein
    3. detoxification
  5. Describe the pathology of cirrhosis of the liver.
    1. Laennec's (portal)
    2. biliary
  6. Describe the gallbladder and its function.
  7. Describe the anatomy of the biliary tree and the sphincters.
  8. Describe the formation of gallstones.
  9. Describe the pancreas in terms of:
    1. position
    2. duct system
    3. exocrine secretions
    4. endocrine secretions
    5. "diabetes mellitus" relationships


OBJ. 1. Describe the shape and position of the normal liver.

Location of the Liver

The liver, the largest internal organ in the body, is situated under the diaphragm. It is further protected by the costal cartilage of the ribs. The liver is so large that it occupies most of the right hypochondrium as well as part of the abdomen. It is, for the most part, covered by peritoneum and entirely by connective tissue. The upper surface of the organ fits nicely against the undersurface (inferior aspect) of the diaphragm.

There are, on the surface, four lobes: right, left, caudate and quadrate. The Falciform ligament divides the liver into two main lobes, right and left, with the right lobe being the larger and is sub- divided into the right lobe proper, the caudate lobe and the quadrate lobe.

The undersurface of the liver, also known as the visceral surface, is more irregular in appear- ance than is the domed convex uppersurface. This irregularity is caused by the fact that the infe- rior surface is in contact with:

  1. the lower esophagus
  2. the stomach, and
  3. the right kidney and adrenal gland
. (See Figure 1)


1. Briefly describe the arrangement of the liver's lobes.

2. Why is the undersurface of the liver so irregular?


1. The liver has two main lobes due to the falciform ligament which divides it. The left lobe is smaller than the right which is further subdivided into the caudate and quadrate lobes.

2. The undersurface is so irregular because this visceral surface is in contact with the lower esophagus, the stomach, the right kidney and the adrenal gland.


OBJ. 2. Describe the following in terms of location, structure and function.
a. liver lobule
b. portal triad
c. venous drainage of the liver
d. hepatic artery
e. hepatic portal vein

OBJ. 3. Describe the major features of the hepatic portal system.

Location, Structure and Function of the Liver

The liver is essential for life, yet it can suffer extensive damage before malfunction becomes pronounced. Although functionally complex, histologically, the liver is nothing more than a greatly modified tubular gland.

Surrounded by a fibrous capsule, the liver is made up of liver lobules (the functional units of the liver). Each lobule is constructed around a central vein that empties into the right and left hepatic veins which then drain into the vena cava.

The lobule is composed of cellular plates that radiate from the central vein. Each cellular plate is two cells thick and between the two cells are small bile canaliculi that empty into terminal ducts.

To summarize, the internal structure of the liver is based on an arrangement of liver cells into a lobule. The lobule is composed of liver cells, as well as liver sinusoids lined with endothelial bile passageways and, at the lobule's periphery, blood vessels. (Note the following illustration.) Blood enters the liver from two sources, the hepatic portal vein (do not confuse with hepatic vein) and the hepatic artery. The hepatic portal vein is the venous drainage for the large and small intestine, the stomach and terminal esophagus and the spleen. Since the function of the spleen is to filter out worn out and broken down red blood cells, the splenic vein of the hepatic portal sys- tem carries the products of red cell breakdown to the liver. The mesenteric veins (they drain the large and small intestine) carry deoxygenated blood and the products of intestinal digestion and absorption (amino acids, mono and disaccharides and short chain fatty acids; long chain fatty acids are absorbed via the lymphatic system). Outside the liver these veins come together to form the hepatic portal vein. About 60% of the blood perfusing the liver is from the hepatic portal vein. Entering the liver next to the hepatic portal vein is the hepatic artery. This supplies about 40X of the perfusing blood. These two vessels remain separate in their passage through the liver until they reach the lobule. At each corner of the hexagonal liver lobule is a group of three structures: a branch of the hepatic portal vein, a branch of the hepatic artery, and a bile duct. These three struc- tures comprise the portal triad. As the two blood vessels leave the portal triad, they empty into the sinusoids. This is a large endothelial lined space and in it the blood from the two sources begins to mix. It percolates through the sinusoids toward the center of the lobule where the central vein is located. It passes through a series of veins that collect from many lobules to enter the right and left hepatic veins which empty into the inferior vena cava. Recall the closeness of the opening of the hepatic-veins to the termination of the inferior vena cava in the right atrium.

Some further comments are now in order:

l. Portal venules receive blood via the portal veins. These venules empty into either liver sinusoids (located between the cell plates) or into the central vein.

2. Hepatic arterioles are also seen within the interlobular septae. These arterioles provide arterial blood to the septal tissues and may empty into the sinusoids.

3. The venous sinusoids are lined with two different cell types:

  1. endothelial cells - have large pores, allows H2O and plasma proteins to pass freely.
  2. Kupffer cells - reticuloendothelial cells capable of phagocytizing bacteria and other foreign matter in the blood.

4. The average rate of blood flow through the liver is 1400 ml/min. Measured pressure in the hepatic vein, however, is normally 0 mm Hg, while in the portal vein the pressure is 8 mm Hg. The elevated portal venous and capillary pressures make the liver more susceptible than other organ systems to increases in resistance to circulation; e.g. cirrhosis of the liver. The Hepatic Portal System The liver receives a dual blood supply:

  1. from the hepatic artery
  2. from the portal vein

You will recall that the portal vein carries blood to the sinusoids of the liver from the alimentary canal.

One of the three branches of the celiac trunk (off the aorta) is the hepatic artery. The hepatic artery enters the substance of the liver in front of (anterior to) the portal vein and to the left of the bile duct. Once the artery enters the liver it divides into the left and right hepatic arteries.

The portal vein, arising from the gut, enters the substance of the liver behind not only the bile duct but also the hepatic artery. At the hilum of the liver (portal hepatis) the vein divides into left and right branches.

The inferior vena cava receives blood from the liver via a series of hepatic veins which drain the central vein. The hepatic vein series can be enumerated as follows:

1. left hepatic v. - drains left lobe
2. middle hepatic v. - drains central portion and may join the left branch to form a common trunk
3. right hepatic v. - drains most of the right lobe

OBJECTIVES 2, 3 Questions

1. Describe what is meant by a portal triad.

2. What types of cells are found in venous sinusoids and what do they do?

3. Describe the arterial supply of blood to the liver.


1. A portal triad is an arrangement of three structures within the liver lobule. At the corner of the hexagonally arranged lobule the following structures are seen together:

  1. branch of hepatic portal vein
  2. branch of hepatic artery
  3. bile duct

2. There are two types of cells present within the venous sinusoids. the endothelial cells and the Kupffer cells. The endothelial cells have very large pores which allow for H20 and plasma proteins to pass. The Kupffer cells on the other hand are reticulo-endothelial cells capable of phagocytizing foreign matter in blood.

3. Off the abdominal aorta is a main arterial trunk called the celiac trunk. A branch of the celiac trunk is the hepatic artery. Once the hepatic artery enters the substance of the liver, it divides into the left hepatic and right hepatic arteries.


OBJ. 4. Describe the following functions of the liver:

a. production of bile
b. production of plasma proteins
c. detoxification

Functions of the Liver

Although this section focuses on the activities of the liver with respect to bile and plasma pro- teins, and the process of detoxification, it should be pointed out that the liver has other functions as well. These functions include:

  1. carbohydrate storage
  2. amino acid metabolism
  3. metabolism of steroidal hormones
  4. metabolism of fat

Bile is a complex solution secreted by the cells of the liver into the bile duct. Approximately 250-1000 ml/day are secreted. It is golden yellow in color due to the presence of bile pigments (bilirubin and biliverdin). These pigments, it should be noted, are the breakdown products of hemoglobin. Also found in bile are the bile salts which are sodium and potassium salts of bile acids.

Bile, containing the substances just mentioned as well as cholesterol, phospholipids, water, Na, K, C1, Ca, and HCO, is secreted into the bile duct which eventually drains into the duodenum. D3uring periods where the digestive processes are somewhat slowed, as in between meals, the duodenal orifice of the duct is closed, causing the bile to “back ups and eventually enter the gall- bladder where it is stored.

Bile is formed by the liver cells (the liver cells are epithelial cells), and excreted into tiny bile canaliculi located between the cells. Bile does not enter the sinusoids. Instead, the canaliculi come together at the portal triad where the portal ductule is formed. These bile ductules coalesce as they approach the surface of the liver (near where the hepatic portal vein and the hepatic artery enter) to form the hepatic duct which emerges from the inferior surface of the liver.

When food enters the duodenum, cholecystokinin is released from the intestinal mucosa which will cause gallbladder contraction, leading to the secretion of bile into the small intestine. Bile is an active emulsifying (suspension of fats) agent and thus plays a part in the digestion and absorp- tion of fat from the intestine.

The second item to be considered is the production of plasma proteins. The liver plays an intricate role in the synthesis of these plasma proteins and is able to provide for an interconversion (i.e. converting one type of amino acid to another by the process of transamination) of amino acids which, you will recall, are the “building blocks” of protein structures. The source of the amino acids necessary for this plasma protein production are:

  1. metabolic turnover of proteins
  2. dietary proteins
  3. glucose (glucogenic amino acids)

Because proteins are stored for only limited periods of time, any imbalance between the amino acids required and those which are available is handled quite readily by the liver’s amino acid interconversion capability.

Two major categories of proteins produced by the liver are the albumins and the globulins. The albumins are large colloidal protein molecules which have an influence on osmotic pressure, plasma volume and tissue fluid balance. The globulins are involved in many functions such as: the transport of several key substances (iron, copper, lipids); serving as a precursor to fibrin (fibrino- gen); serving as antibodies or immunoglobins (Gamma globulin, IgG, IgE, IgA, IgD, IgM).

Furthermore, several proteins concerned with blood coagulation are produced by the liver, such as:

  1. Fibrinogen
  2. Prothrombin
  3. Factor VII
  4. Factor IX
  5. Factor X

Another function of the liver is detoxification. You will recall from an earlier pharmacology mini- course that in this process, which can manifest itself as either conjugation, oxidation, or reduction, the liver metabolizes the by-products of cellular metabolism and exogenous materials such as drugs. Of particular importance is the removal of ammonia which is toxic to the human organism. This ammonia is removed from amino acids via deamination and converted to a normally non- toxic material called urea. Urea, which has the following structure: is formed during a series of reactions called the urea cycle (Krebs-Henseleit cycle) and is excreted in the urine. Because of the vast enzyme system of the liver, this organ plays an important role in drug metabolism. Knowledge of how a drug is handled by the liver is very important in therapeu- tics. As one can imagine, liver damage must be taken into account when drugs that are metabo- lized in the liver are given to a patient. Not all types of liver disease affect drug metabolism equally, since drug metabolism is not uniform throughout the liver. However, those disease states which damage areas which actively metabolize drugs can have serious consequences. In order for a patient’s ability to metabolize drugs to be compromised, the liver parenchymal cells surrounding the central vein must be damaged. In some cases, such as liver damage associated with alcohol- ism, this area is not damaged and there is little change in the drug metabolizing capabilities. On the other hand, toxic substances like carbon tetrachloride (CC14), a cleaning fluid, specifically damages the parenchymal cells surrounding the central vein and, therefore, severely compromises an individual’s drug metabolizing capacity.


1. Describe bile in terms of its:
  1. constituents
  2. function

2. Name the plasma proteins produced by the liver which are involved in blood coagulation.
3. Which proteins formed by the liver are important to the immune system?
4. What is the most important compound detoxified by the liver under normal circumstances?


1. Bile is a complex solution composed of the bile pigments (bilirubin and biliverdin), bile salts, sodium, potassium, chloride, calcium, cholesterol, water. When bile enters the duodenum, the bile salts act to separate the fat droplets via a process called emulsification. This emulsification process aids in the digestion and absorption of fats.
2. The liver produces the following plasma proteins involved in blood coagulation:
  1. Fibrinogen
  2. Prothrombin
  3. Factor VII
  4. Factor IX
  5. Factor X

3. Gamma globulin IgE, IgA, IgG, IgD and IgM.
4. Ammonia. It is removed by the metabolic breakdown of drugs and amino acids and is converted into urea.


OBJ. 5. Describe the pathology of cirrhosis of the liver:

  1. Laennec's (portal)
  2. Biliary

Cirrhosis of the Liver

The term cirrhosis denotes chronic tissue degeneration in which cells are destroyed leading to the formation of fibrous scar tissue. As the cellular destruction continues, blood, lymph and bile channels within the liver become distorted and compressed, leading to intrahepatic congestion, portal hypertension and impaired liver function. The fibrous changes within the organ cause it to become firmer and smaller. The surface, however, becomes rough and bumpy because of the development of nodules on the surf ace of the organ. The nodules are regenerated hepatic cells.

The two types of cirrhosis considered in this objective have the following distinguishing characteristics:

  1. Laennec's portal cirrhosis
    1. scar tissue surrounds portal area
    2. most commonly due to chronic alcoholism
  2. Biliary
    1. scarring around bile ducts and lobes of liver
    2. rarer than Laennec's cirrhosis

Fatty changes in the liver occur under a variety of conditions and may vary from a mild condition seen in caloric restriction to severe forms such as is seen in chronic alcoholism. The fatty metamorphosis seen in liver disorders is not generally a fatty infiltration from non-hepatic sources, but is a deposition of fat resulting from deranged hepatocyte lipid metabolism. It is a common sequela of a large number of liver disorders including infections and intoxications.

The prolonged passive congestion of right-sided heart failure tends to cause fatty change due to venous congestion involving the inferior vena cava, the hepatic vein and the intrahepatic veins retrograde to the central lobular vein. Because the liver cells surrounding the central vein normally are poorly oxygenated, they are especially susceptible to damage due to hepatic vein congestion.

It is important to remember that cirrhosis is a chronic progressive disease and, although it may be halted in some of its stages, the damage that has already occurred is not reversible. Cirrhosis is the result of a fibroplasia that leads to extensive scarring. The etiology is unknown although there is usually associated with it liver cell changes or destruction is unable to inactivate estrogens which leads to testicular atrophy. Spider nevi and palmar erythema may be due to a deficiency of the B- complex vitamins.

Splenomegaly is due to obstruction of the splenic vein, one of the two major veins forming the hepatic portal vein.

Biliary cirrhosis is less common and is due to an obstruction in the bile duct system, such as would be created by a gallstone. It does not destroy the liver as rapidly as portal cirrhosis, but it is also a serious disorder and is one of the causes of jaundice. In this particular situation, it would be called obstructive jaundice. The jaundice or yellowish tint to the body is caused by the blocked excretion of bilirubin at the level of the bile ducts and its return to the bloodstream.


1. Briefly compare Laennec's and biliary cirrhosis.
2. What are some of the symptomatic changes which occur due to cirrhosis?


1. In Laennec's cirrhosis, common in chronic alcoholism, fatty deposits eventually lead to the development of fibrous scar tissue which surrounds the portal area. In biliary cirrhosis scarring occurs around the bile ducts and lobes of the liver and may lead to jaundice.
2. Some of the symptomatic changes which are seen in cirrhosis are: ascites, esophageal varices, ulcer, hypovitaminosis and splenomegaly.


OBJ. 6. Describe the gallbladder and its function.

OBJ. 7. Describe the anatomy of the biliary tree and the sphincters.

The Gallbladder

A structure which looks somewhat like a pear lies on the under or visceral surface of the liver. It is called the gallbladder and is composed of three portions termed the neck, the body, and the fundus. The following diagram illustrates the position of the gallbladder 2nd surrounding structures. The inner lining of the gallbladder resembles somewhat that of the stomach with Its rugae and is composed of mucous membranes. The gallbladder serves as a reservoir for bile produced by the liver. As the gallbladder fills the rugae allow it to enlarge and assume its pear-shape appearance. The gallbladder has a capacity of approximately 50 ml of bile. This structure receives its arterial supply from the cystic artery while the cystic vein drains the gallbladder directly into the portal vein. It should be remembered that the cystic artery is a branch of the right hepatic artery. The gallbladder receives its nerve supply via the celiac plexus.

The Biliary Tree and the Sphincters

The left and right hepatic ducts descend from the undersurface of the liver and unite to form the handle of the sling-shot called the common hepatic duct.

This structure is then joined by the cystic duct. Thus, the union of the cystic duct with the hepatic ducts forms the common bile duct. This latter structure has a length of about 4-6 cm for it must extend to the second portion of the duodenum. At this point, where it enters the duodenum, it is located slightly above and behind the pancreatic duct which is also entering this portion of the duodenum.

Located at the base of the common bile duct is the sphincter of Oddi. Normally this sphincter is in a contracted or closed configuration. However, under the influence of cholecystokinin, the sphinc- ter dilates to allow for the passage of bile into the duodenum. You will recall that:

            fats within duodenum

                   ACT TO

stimulate cholecystokinin production by duodenum which

                  ACTS TO

cause gallbladder contraction and ejection of bile.

Bile salts are constituents of bile which aid in the digestion of fats via a process called emulsification.

In summary:

  1. Bile is continually secreted by the liver.
  2. Approximately 50 ml of bile may be stored in the gallbladder.
  3. Upon gallbladder contraction - bile passes from the gallbladder --> cystic duct --> common bile duct ---> to the duodenum.
  4. Bile is composed of bile salts, cholesterol, H20, bilirubin, phospholipids, Na, K, C1, Ca, HCO3.
  5. Bile salts 1. cause fat emulsification 2. help in fatty acid absorption
  6. Without bile salts - no fat soluble vitamins (A, D, E, K) are absorbed. No vitamin K leads to Factor VII, IX, X, and prothrombin deficiency which leads to coagulation difficulties.

OBJECTIVE 6 Question

Describe the sequence of events which cause bile to be ejected from the gallbladder.


When fats are present within the duodenum, they will stimulate the intestinal mucosa to secrete a substance called cholecystokinin. This cholecystokinin causes gallbladder contraction. When the gallbladder contracts, bile is ejected into the cystic duct which joins the hepatic duct to form the common bile duct which carries bile to the duodenum. Relaxation of the sphincter of Oddi allows for the passage of bile into the duodenum.


OBJ. 8. Describe the formation of gallstones.


A gallstone is actually a stone-like mass called a calculus, which forms in the gallbladder. This condition has the medical term cholelithiasis. There is a high incidence of this condition in people over 40 and it accounts for much of the cholecystitis seen in the primary care clinic. Some underlying causes include: pregnancy, obesity, diabetes, and cholecystitis. In the United States, about 10 to 20 percent of the adult population has gallstones. They are rare in the first two decades of life. The four F's fat, female, fertile (multiparous), and forty characterize the population with the highest incidence. Although gallstones may form anywhere in the biliary tract, the majority are found in the gallbladder. In about 80 percent of cases cholesterol is the chief component of gallstones. Cholesterol stones are classically 1 to 5 cm. in diameter, pale yellow, round or oval and often translucent. Also found are pigment stones composed of calcium bilirubin. These stones are usually associated with a hemolytic disorder. They are jet-black. Mixed stones contain calcium carbonate as well as calcium bilirubin.

The genesis of cholesterol stones is something of a mystery. However, the relative proportion of cholesterol, bile acids and phospholipids (chiefly lecithin) is of critical importance. If the ratio of bile acid plus lecithin to cholesterol falls below a certain level, the bile becomes supersaturated with cholesterol, and gallstone formation may occur.

Because gallstones occur commonly, they are sometimes squeezed into the common bile duct where they may enter the duodenum. Sometimes, however, they may obstruct this duct which can cause pain from distention and spasm of the biliary tract.

OBJECTIVE 8 Questions

1. Describe how cholesterol gallstones are thought to be formed.
2. In which patients are gallstones most frequently seen?


1. When the ratio of bile acid plus lecithin to cholesterol falls, bile becomes supersaturated with cholesterol and gallstones may form.

2. Gallstones are most frequently found in patients over 40 years of age. They are more prevalent in females who are obese. Gallstones are also more frequent in patients with hemolytic disorders.


OBJ. 9. Describe the pancreas in terms of:

  1. position
  2. duct system
  3. exocrine secretion
  4. endocrine secretion
  5. "diabetes mellitus" relationships

The Pancreas

The pancreas is an unusual structure in that it is both exocrine and endocrine in function. This very diffuse structure lies slightly below and behind the stomach.

Various pancreatic secretions which participate in the digestive process flow (from the exocrine portion of the pancreas) down the main pancreatic duct, the duct of Wirsung. This duct, in many people, joins the common bile duct prior to its entrance into the duodenum. The exocrine secretions of the pancreas include:

  1. lipase
  2. amylase
  3. trypsin
  4. carboxypeptidase

The endocrine portion, on the other hand, consists of packets or groups of cells called the islets of Langerhans. The islets are composed of two types of cells:

  1. alpha cells - secrete glucagon
  2. beta cells - secrete insulin

Insulin decreases blood glucose level by stimulating the cellular uptake and the metabolism of glucose. In contrast, glucagon increases the blood glucose level by stimulating the conversion of glycogen to glucose in the liver. The rate of their secretion is directly controlled by the concentration of glucose in the blood. Thus, it can be discerned that insulin is directly involved in carbohydrate metabolism, as follows:


              increased blood sugar levels


       beta cell stimulation ---> insulin secretion 


         increase glucose metabolism --->  ATP yielded or glucose stored as glycogen


        reduction of blood glucose levels

Glucagon on the other hand exists as an insulin antagonist in that it increases blood sugar levels by increasing glycogen breakdown into glucose. Thus, the glucagon-insulin balance is important in maintaining proper blood glucose levels.

Diabetes mellitus is a disease which is a generalized chronic metabolic disorder involving carbo- hydrate metabolism, specifically glucose. This disorder usually develops in subjects as a heredi- tary disorder and is manifested in the fully developed form by:

  1. weakness
  2. lassitude
  3. loss of weight
  4. hyperglycemia (high blood sugar)
  5. ketosis
  6. acidosis
  7. protein breakdown
  8. glycosuria
  9. and much, much more.

Although other factors may play a part in the disease, diabetes is probably mainly due to inadequate insulin secretion by the beta cells. The major threats to the diabetic patient arise from the disease's surrounding complications, especially those associated with severe metabolic abnormalities resulting in ketoacidosis as well as complications such as:

  1. retinitis
  2. renal failure
  3. hypertension
  4. neuropathy
  5. premature atherosclerosis

OBJECTIVE 9 Questions

1. Describe the anatomy of the duct of Wirsung and the components transported by it.
2. Describe the main histological cells of the pancreas which produce endocrine hormones.
3. What physiological function is performed by insulin and glucagon?
4. Describe diabetes mellitus with respect to the pancreas.

OBJECTIVE 9 - Answers

1. The duct of Wirsung is the main pancreatic duct which, in many people, joins the common bile duct. Through it the excretory enzymes of the pancreas empty into the duodenum. These enzymes are lipase, amylase, trypsin, and carboxypeptidase.

2. The endocrine tissue of the pancreas consists of groups of cells called islets of Langerhans. There are two main types of cells which make up the islets:

  1. Alpha cells - secrete glucagon
  2. Beta cells - secrete insulin

3. Both insulin and glucagon are implicated in modulating carbohydrate metabolism. The main influence of insulin is to increase glucose metabolism and to store glucose as glycogen. Glucagon is an antagonist of insulin in that it increases blood glucose via glycogen breakdown in the liver.

4. Diabetes mellitus is a genetic disease in which there is a defect of insulin release from the pancreas. The clinical manifestations are: hyperglycemia, ketosis, acidosis, protein breakdown, lassitude, and frequently a loss of weight.