Ketoacidosis, cause

NIDDM is a much more common disease than IDDM, accounting for about 85—90% of all cases of diabetes meUitus. Whereas NIDDM may be present at any age, the incidence increases dramatically with advanced age over 10% of the population reaching 70 years of age has NIDDM. Patients with NIDDM do not require insulin treatment to maintain life or prevent the spontaneous occurrence of diabetic ketoacidosis. Therefore, NIDDM is frequendy asymptomatic and unrecognized, and diagnosis requires screening for elevations in blood or urinary sugar. Most forms of NIDDM are associated with a family history of the disease, and NIDDM is commonly associated with and exacerbated by obesity. The causes of NIDDM are not well understood and there may be many molecular defects which lead to NIDDM. 

Insulin is necessary for controlling type 1 diabetes mellitus that is caused by a marked decrease in the amount of insulin produced by die pancreas. Insulin is also used to control the more severe and complicated forms of type 2 diabetes mellitus. However, many patients can control type 2 diabetes with diet and exercise alone or with diet, exercise, and an oral antidiabetic drug (see section Oral Antidiabetic Dmgp ). Insulin may also be used in the treatment of severe diabetic ketoacidosis (DKA) or diabetic coma. Insulin is also used in combination with glucose to treat hypokalemia by producing a shift of potassium from die blood and into die cells. 

Increased fatty acid oxidation is a characteristic of starvation and of diabetes meUims, leading to ketone body production by the Ever (ketosis). Ketone bodies are acidic and when produced in excess over long periods, as in diabetes, cause ketoacidosis, which is ultimately fatal. Because gluconeogenesis is dependent upon fatty acid oxidation, any impairment in fatty acid oxidation leads to hypoglycemia. This occurs in various states of carnitine deficiency or deficiency of essential enzymes in fatty acid oxidation, eg, carnitine palmitoyltransferase, or inhibition of fatty acid oxidation by poisons, eg, hypoglycin. 

Higher than normal quantities of ketone bodies present in the blood or urine constitute ketonemia (hyperke-tonemia) or ketonuria, respectively. The overall condition is called ketosis. Acetoacetic and 3-hydroxybutyric acids are both moderately strong acids and are buffered when present in blood or other tissues. However, their continual excretion in quantity progressively depletes the alkah reserve, causing ketoacidosis. This may be fatal in uncontrolled diabetes mellitus. 

Diabetic ketoacidosis A reversible but life-threatening short-term complication primarily seen in patients with type 1 diabetes caused by the relative or absolute lack of insulin that results in marked ketosis and acidosis. 

Hyperosmolar hyperglycemic state A potentially fatal short-term complication most commonly seen in older patients with type 2 diabetes caused by an insufficiency of insulin action that leads to alterations of osmolality and hyperglycemia, but without the ketosis and acidosis seen in diabetic ketoacidosis. 

Like ketoacidosis, respiratory acidosis can also upset the acid-base balance in the body. Respiratory acidosis occurs when the lungs cannot remove enough carbon dioxide from the body. This may be due to severe lung diseases such as chronic asthma, emphysema, or bronchitis, or it could be caused by mechanical restrictions to the emptying of the lung due to scoliosis (curvature of the spine) or severe obesity. 

The following factors have been suggested as alternatives to consider when presented with a potential case of exposure to carbon monoxide diabetic ketoacidosis, hypothyroidism and myxedema coma, labyrinthitis, and lactic acidosis toxic exposures resulting in methemoglobinemia ingestion of alcohols or narcotics and diseases that cause gastroenteritis, encephalitis, meningitis, and acute respiratory distress syndrome. 

Tildon, J. T. and Cornblath, M. Succinyl-CoA 3-ketoacid CoA-transferase deficiency. A cause for ketoacidosis in infancy. /. Clin. Invest. 51 493 98,1972. 

In patients with type 1 insulin-dependent diabetes mellitus not adequately treated with insulin, fatty add release from adipose tissue and ketone synthesis in the liver exceed the ability of other tissues to metabolize them, and a profound, life-threatening ketoaddosis may ocxnir. An infection or trauma (causing an increase in cortisol or epinephrine) may predpitate an episode of ketoaddosis. Patients with type 2 non-insulin-dependent diabetes meUitus (NIDDM) are much less likely to show ketoaddosis. The basis for this observation is not completely understood, although type 2 disease has a much slower, insidious onset, and insulin resistance in the periphery is usually not complete. Type 2 diabetics can develop ketoacidosis after an infection or trauma. In certain populations with NIDDM, ketoaddosis is much more common than previously appredated. 

If the production of ketone bodies exceeds the demand for them outside the liver, there is an increase in the concentration of ketone bodies in the plasma (ketonemia) and they are also eventually excreted in the urine (ketonu-ria). Both phenomena are observed after prolonged starvation and in inadequately treated diabetes mellitus. Severe ketonuria with ketoacidosis can cause electrolyte shifts and loss of consciousness, and is therefore life-threatening (ketoacidotic coma). 

L A. Metformin causes lactic acidosis in patients with renal failure and severe congestive heart failure. It does not increase the risk of ketoacidosis and showed a reduction in cardiovascular comorbidities in a large study. It is contraindicated in patients with severe liver disease but does not cause hepatic necrosis. When used as monotherapy, metformin rarely causes hypoglycemia. 

Overdose may cause hyperglycemia or ketoacidosis manifested as increased urination, thirst, and fruitlike breath odor. 

For persons with type 1 diabetes, insulin replacement therapy is necessary to sustain life. Pharmacologic insulin is administered by injection into the subcutaneous tissue using a manual injection device or an insulin pump that continuously infuses insulin under the skin. Interruption of the insulin replacement therapy can be life-threatening and can result in diabetic ketoacidosis or death. Diabetic ketoacidosis is caused by insufficient or absent insulin and results from excess release of fatty acids and subsequent formation of toxic levels of ketoacids. 

However, short-acting, regular soluble insulin is the only type that should be administered intravenously because the dilution causes the hexameric insulin to immediately dissociate into monomers. It is particularly useful for intravenous therapy in the management of diabetic ketoacidosis and when the insulin requirement is changing rapidly, such as after surgery or during acute infections. 

Normally, the sum of the cations exceeds the sum of the anions by no more than 12-16 mEq/L (or 8-12 mEq/L if the formula used for estimating the anion gap omits the potassium level). A larger-than expected anion gap is caused by the presence of unmeasured anions (lactate, etc) accompanying metabolic acidosis. This may occur with numerous conditions, such as diabetic ketoacidosis, renal failure, or shock-induced lactic acidosis. Drugs that may induce an elevated anion gap metabolic acidosis (Table 58-1) include aspirin, metformin, methanol, ethylene glycol, isoniazid, and iron. 

Allyl isovalerate has low irritancy potential. It is deduced that one of its metabolites, isovaleric acid, is toxic, based upon the effects of an inborn error of leucine metabolism caused by isovaleiy l-coenzynie A dehydrogenase deficiency. This is a sx ndrome of neonatal vomiting and lethargy progressing to coma, pancytopenia and ketoacidosis that can be alleviated by glycine treatment, which enhances the synthesis and excretion of iso-valerylglycine (Cohn et al., 1978 lARC, 1985). 

Ition of the ketone bodies may be as high as 5000 mg/24 hr, and the blood concentration may reach 90 mg/dl (versus less than 3 mg/dL in normal individuals). A frequent symptom of diabetic ketoacidosis is a fruity odor on the breath which result from increased production of acetone. An elevation of the ketone body concentration in the blood results in acidemia. [Note The carboxyl group of a ketone body has a pKa about 4. Therefore, each ketone body loses a proton (H+) as it circulates in the blood, which lowers the pH of the body. Also, excretion of glucose and ketone bodies in the urine results in dehydration of the body. Therefore, the increased number of H+, circulating in a decreased volume of plasma, can cause severe acidosis (ketoacidosis)]. Ketoacidosis may also be seen in cases of fasting (see p. 327). 

The three compounds, acetoacetate, acetone, and 3-hydroxybutyrate, are known as ketone bodies.60b The inability of the animal body to form the glucose precursors, pyruvate or oxaloacetate, from acetyl units sometimes causes severe metabolic problems. The condition known as ketosis, in which excessive amounts of ketone bodies are present in the blood, develops when too much acetyl-CoA is produced and its combustion in the critic acid cycle is slow. Ketosis often develops in patients with Type I diabetes mellitus (Box 17-G), in anyone with high fevers, and during starvation. Ketosis is dangerous, if severe, because formation of ketone bodies produces hydrogen ions (Eq. 17-5) and acidifies the blood. Thousands of young persons with insulin-dependent diabetes die annually from ketoacidosis. 

A closely related disease is caused by a deficiency of propionyl-CoA carboxylase.3 This may be a result of a defective structural gene for one of the two subunits of the enzyme, of a defect in the enzyme that attaches biotin to carboxylases, or of biotinitase, the enzyme that hydrolytically releases biotin from linkage with lysine (Chapter 14). The latter two defects lead to a multiple carboxylase deficiency and to methylmalonyl aciduria as well as ketoacidosis and propionic acidemia. ... 

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